HRP920903A2

HRP920903A2 - Indenoindole compounds and a process for preparing the same

Info

Publication number: HRP920903A2
Application number: HRP920903AA
Authority: HR
Inventors: Malcolm Sainsbury; Howard G. Shertzer
Original assignee: University Of Bath; University Of Cincinnati
Priority date: 1989-06-22
Filing date: 1992-10-02
Publication date: 1994-04-30
Also published as: WO1990015799A1; MY107311A; PL285752A1; SE8902274D0; IE74682B1; SI9011223A; PL167761B1; EP0409410B1; IL94830A; LV10253A; RU2104270C1; HUT59097A; GR3019779T3; LV10253B; DD297960A5; CA2060897A1; NZ234175A; EP0409410A1; JP3064411B2; NO177932B

Abstract

Compounds of the formula <CHEM> wherein R is hydrogen or a lower alkyl group or COR<1><5> R<1>, R<2>, R<1><1> and R<1><2>, are hydrogen or a lower alkyl group, R<3>, R<4>, R<5> and R<6> are hydrogen, hydroxy, halogen, a lower alkyl group, a lower alkoxy group or a mono- or di-lower alkyl amino group, NH2 or NR<1><3>COR<1><4>, R<7>, R<8>, R<9> and R<1><0> are hydrogen, hydroxy, a lower alkyl group, a lower alkoxy group, a mono- or di-lower alkylamino group, or NH<1><3>COR<1><4> wherein R<1><3>, R<1><4> and R<1><5> are hydrogen or a lower alkyl group, enantiomers and salts thereof, with the proviso that when R is COR<1><5> then at least one of R<3> to R<1><0> are hydroxy or a mono or di-lower alkylamino group, are useful as antioxidants, within the medical and non-medical field. Many of the compounds of formula IA and IB are new and various methods for preparing them are described.

Description

Sadašnji izum odnosi se na novi tip hidrofobnog antioksidansa, na osnovi strukture indenoindola, koji je vrlo efikasan u reduciranju, tj. gašenju slobodnih radikala u lipidima i lipidnim bifazama, s čime zaustavlja proces peroksidacije lipida, te sprječava stanja i oboljenja koja nastaju preko ovih ili sličnih procesa. Izum se također odnosi na preparate, posebno farmaceutske preparate, koji sadrže barem jedan spoj iz izuma, ili njegovu sol, posebno farmaceutski prihvatljivu sol, kao aktivni sastojak. U drugom pogledu, izum se odnosi na postupke za dobivanje takvih spojeva i na korištenje aktivnih spojeva u medicinskoj terapiji, kao i u izvanmedicinskoj primjeni. Posebno važnu izvanmedicinsku primjenu predstavljalo bi korištenje u kontroli ili prekidanju procesa koji se posreduju preko slobodnih radikala. The present invention relates to a new type of hydrophobic antioxidant, based on the structure of indenoindole, which is very effective in reducing, i.e. extinguishing, free radicals in lipids and lipid biphases, thereby stopping the process of lipid peroxidation, and preventing conditions and diseases that arise through these or similar processes. The invention also relates to preparations, especially pharmaceutical preparations, which contain at least one compound from the invention, or its salt, especially a pharmaceutically acceptable salt, as an active ingredient. In another aspect, the invention relates to methods for obtaining such compounds and to the use of active compounds in medical therapy, as well as in non-medical applications. A particularly important non-medical application would be the use in the control or interruption of processes mediated by free radicals.

Stanje tehnike State of the art

Izvjesni biološki procesi dovode do stvaranja manje ili više stabilnih intermedijera sa nesparenim elektronom, koji se može ili predati, ili spariti sa dodatnim elektronom iz okoline. Takvi intermedijeri zovu se još i slobodni radikali i mogu se javiti kao proizvodi različitih ecimskih i ne-encimskih reakcija od kojih su neke zdrave za funkcioniranje organizma, npr. redukcija ribonukleotidnih difosfata radi sinteze DNK i izgradnja prostaglandina u reakciji za njegovu sintezu. Ova posljednja reakcija vrlo je bitna u inflamatornoj reakciji do koje dolazi nakon povrede stanica, kao u brojnim drugim funkcijama. Druge reakcije s radikalima uključuju mieloperoksidaznu reakciju u neutrofilima i makrofazima koji uništavaju bakterije i druge napadalačke čestice, kao i prijevoz elektrona u mitohondrijskom respiratornom lancu. Najveći broj organizama sadrži kemijske antioksidanse kao što su alfa-tokoferol (vitamin E), askorbinska kiselina i različiti radikali i encimi koji dezaktiviraju peroksidaze, npr. dismutaza superoksida, katalaza i glutationska peroksidaza. Certain biological processes lead to the creation of more or less stable intermediates with an unpaired electron, which can either be donated or paired with an additional electron from the environment. Such intermediates are also called free radicals and can appear as products of various enzymic and non-enzymic reactions, some of which are healthy for the functioning of the organism, for example, the reduction of ribonucleotide diphosphates for DNA synthesis and the construction of prostaglandins in the reaction for its synthesis. This last reaction is very important in the inflammatory reaction that occurs after cell injury, as in numerous other functions. Other reactions with radicals include the myeloperoxidase reaction in neutrophils and macrophages that destroy bacteria and other invading particles, as well as electron transport in the mitochondrial respiratory chain. The largest number of organisms contain chemical antioxidants such as alpha-tocopherol (vitamin E), ascorbic acid and various radicals and enzymes that deactivate peroxidases, eg superoxide dismutase, catalase and glutathione peroxidase.

Slobodni radikali različitih vrsta se sve češće povezuju sa širokim spektrom stanja i oboljenja, kao što su izokemične ili reperfuzijske povrede, arterioskleroza, tromboza i embolizam, alergijska/inflamatorna stanja kao što je bronhijalna astma, reumatski artritis, stanja povezana s Alzhajmerovom bolešću, Parkinsonovom bolešću i starenjem, kataraktom, dijabetesom, neoplazmama i toksičnost anti-neoplastnih i imunosupresivnih sredstava i kemikalija. Jedno od mogućih obrazloženja za ova stanja i oboljenja i da, iz nepoznatih razloga, endogena zaštitna sredstva protiv štetnog djelovanja slobodnih radikala nisu dovoljno aktivna da bi zaštitila tkivo od oštećenja izazvanog radikalima. Peroksidacija lipida, izazvana pretjeranim stvaranjem radikala može predstavljati jedan od važnijih puteva oštećenja kod navedenih stanja i oboljenja. Davanje dodatnih antioksidansa, koji inhibiraju reakcije radikala, npr. peroksidaciju lipida, prema tome može osigurati način za liječenje navedenih stanja i oboljenja. Sadašnji izum opisuje nove antioksidanse indenoindolovog tipa, koji ispunjavaju oba zahtjeva za akumulacijom u membranama, tj. u dovoljnoj mjeri su hidrofobni i predstavljaju jake inhibitore peroksidacije lipida. Ovi novi antioksidansi imaju prednost u usporedbi sa drugim antioksidansima, npr. alfa-tokoferolom. Spojevi iz sadašnjeg izuma mogu se također koristiti i u izvanmedicinskim primjenama, kao stabilizatori za spojeve podložne oksidacijskom razlaganju, npr. u proizvodima za njegu kože, za konzerviranje namirnica, kao dodatak namirnicama i u konzerviranju drugih proizvoda. Sadašnji izum obuhvaća i metodu za stabilizaciju u kojoj se koriste tetrahidroindenoindoli, kao i dobivene stabilizirane preparate. Free radicals of various types are increasingly associated with a wide range of conditions and diseases, such as isochemical or reperfusion injuries, arteriosclerosis, thrombosis and embolism, allergic/inflammatory conditions such as bronchial asthma, rheumatic arthritis, conditions associated with Alzheimer's disease, Parkinson's disease and aging, cataracts, diabetes, neoplasms and the toxicity of anti-neoplastic and immunosuppressive agents and chemicals. One of the possible explanations for these conditions and diseases is that, for unknown reasons, endogenous protective agents against the harmful effects of free radicals are not active enough to protect tissue from damage caused by radicals. Lipid peroxidation, caused by the excessive formation of radicals, can represent one of the most important damage pathways in the aforementioned conditions and diseases. Administering additional antioxidants, which inhibit radical reactions, eg lipid peroxidation, can therefore provide a way to treat the aforementioned conditions and diseases. The present invention describes new antioxidants of the indenoindole type, which fulfill both requirements for accumulation in membranes, i.e. they are sufficiently hydrophobic and are strong inhibitors of lipid peroxidation. These new antioxidants have an advantage compared to other antioxidants, eg alpha-tocopherol. The compounds of the present invention can also be used in non-medical applications, as stabilizers for compounds subject to oxidative decomposition, for example in skin care products, for food preservation, as a food additive and in the preservation of other products. The present invention also includes a method for stabilization in which tetrahydroindenoindoles are used, as well as the obtained stabilized preparations.

N-Metil-4b,5,9b,10-tetrahidroindeno/1,2-b/indol opisan je u J. Chem. Soc. Commun. str. 647-48 (1981). N-Methyl-4b,5,9b,10-tetrahydroindeno/1,2-b/indole is described in J. Chem. Soc. Commun. p. 647-48 (1981).

4b,5,9b,10-Tetrahidro-9b-etiindeno/1,2-b/indol opisan je u Beilstein - ovoj Hadbuch der Organischen Chemie, 4:e Auflage, It. 20 EII, str. 310-311 (1953). 4b,5,9b,10-Tetrahydro-9b-ethyindeno/1,2-b/indole is described in Beilstein - this Hadbuch der Organischen Chemie, 4:e Auflage, It. 20 EII, p. 310-311 (1953).

Opis rješenja tehničkog problema Description of the solution to the technical problem

Otkriveno je da spojevi sa tetrahidroindeno-indolovom strukturom formule IA (THII) i IB (izo-THII) predstavljaju efikasne inhibitore procesa peroksidacije lipida i da su korisni kao antioksidansi. IA ili IB mogu se javiti u obliku racemske smjese ili u obliku formule enantiomera formula: It was discovered that compounds with the tetrahydroindeno-indole structure of formulas IA (THII) and IB (iso-THII) represent efficient inhibitors of the lipid peroxidation process and are useful as antioxidants. IA or IB can appear in the form of a racemic mixture or in the form of an enantiomer formula:

[image] [image]

gdje R predstavlja vodik, alkilnu grupu ili COR15; R1, R2, R11 i R12 su nezavisno izabrani od vodika ili nižih alkil grupa; R3, R4, R5 i R6 su nezavisno izabrani od vodika, hidroksi, halogena, nižih alkil grupa, nižih alkoksi grupa, mono- ili di- nižih alkilamino grupa, NH2 ili NR13 COR14; R7, R8, R9 i R10 su nezavisno izabrani od vodika, hidroksi, nižih alkil grupa, nižih alkoksi grupa, mono- ili di-nižih alkilamino grupa, NH2 ili NR13 COR14; R13, R14 i R15 su nezavisno izabrani od vodika, ili nižih alkil grupa, pod uvjetom da, kada R predstavlja COR14, onda barem jedan od R3 do R10 predstavlja hidroksi ili mono- ili di-nižu alkilamino grupu; i njihovih enantiomjera i soli. where R represents hydrogen, an alkyl group or COR15; R 1 , R 2 , R 11 and R 12 are independently selected from hydrogen or lower alkyl groups; R3, R4, R5 and R6 are independently selected from hydrogen, hydroxy, halogen, lower alkyl groups, lower alkoxy groups, mono- or di-lower alkylamino groups, NH2 or NR13 COR14; R 7 , R 8 , R 9 and R 10 are independently selected from hydrogen, hydroxy, lower alkyl groups, lower alkoxy groups, mono- or di-lower alkylamino groups, NH 2 or NR 13 COR 14 ; R 13 , R 14 and R 15 are independently selected from hydrogen, or lower alkyl groups, provided that, when R represents COR 14 , then at least one of R 3 to R 10 represents a hydroxy or mono- or di-lower alkylamino group; and their enantiomers and salts.

Novi spojevi iz sadašnjeg izuma imaju formulu IA ili IB: The new compounds of the present invention have the formula IA or IB:

[image] [image]

gdje R predstavlja vodik, alkil grupu ili COR15; R1, R2, R11 i R12 su nezavisno izabrani od vodika ili nižih alkil grupa; R3, R4, R5 i R6 su nezavisno izabrani od vodika, hidroksi, halogena, nižih alkil grupa, nižih alkoksi grupa, mono- ili di- nižih alkilamino grupa, NH2 ili NR13 COR14; R7, R8, R9 i R10 su nezavisno izabrani od vodika, hidroksi, nižih alkil grupa, nižih alkoksi grupa, mono- ili di-nižih alkilamino grupa, NH2 ili NR13 COR14; R13, R14 i R15 su nezavisno izabrani od vodika ili nižih alkil grupa, pod slijedećim uvjetima: where R represents hydrogen, an alkyl group or COR15; R 1 , R 2 , R 11 and R 12 are independently selected from hydrogen or lower alkyl groups; R3, R4, R5 and R6 are independently selected from hydrogen, hydroxy, halogen, lower alkyl groups, lower alkoxy groups, mono- or di-lower alkylamino groups, NH2 or NR13 COR14; R 7 , R 8 , R 9 and R 10 are independently selected from hydrogen, hydroxy, lower alkyl groups, lower alkoxy groups, mono- or di-lower alkylamino groups, NH 2 or NR 13 COR 14 ; R13, R14 and R15 are independently selected from hydrogen or lower alkyl groups, under the following conditions:

(i) kada je R u formuli IA metil, onda je bar jedan od radikala R1 do R12 različit od vodika; i (i) when R in formula IA is methyl, then at least one of the radicals R1 to R12 is different from hydrogen; and

(ii) kada R predstavlja vodik, a R11 je etil u formuli IA, onda barem jedan od radikala R1 do R10 ili R12 mora biti različit od vodika, ili njegove farmaceutski prihvatljive soli. (ii) when R represents hydrogen and R 11 is ethyl in formula IA, then at least one of the radicals R 1 to R 10 or R 12 must be different from hydrogen, or a pharmaceutically acceptable salt thereof.

Slijedeći spojevi formule IA (THII) i IB (izo-THII), koji su efikasni kao inhibitori procesa peroksidacije lipida, naročito su korisni kao antioksidansi u medicinskoj terapiji: The following compounds of formulas IA (THII) and IB (iso-THII), which are effective as inhibitors of the lipid peroxidation process, are particularly useful as antioxidants in medical therapy:

[image] [image]

gdje R predstavlja vodik, alkil grupu ili COR15; R1, R2, R11 i R12 su nezavisno izabrani od vodika ili nižih alkil grupa; R3, R4, R5 i R6 su nezavisno izabrani od vodika, hidroksi, halogena nižih alkil grupa, nižih alkoksi grupa, mono- ili di-nižih alkilamino grupa, NH2 ili NR13 COR14; R7, R8, R9 i R10 su nezavisno izabrani od vodika, hidroksi, nižih alkil grupa, nižih alkoksi grupa, mono- ili di-nižih alkilamino grupa, NH2 ili NR13 COR14; R13, R14 su nezavisno izabrani od vodika ili nižih alkil grupa, pod uvjetom da, kada R predstavlja COR15, onda bar jedan od R3 do R10 predstavlja hidroksi ili mono- ili di-niži alkilamino; i njihovi enantiomeri i farmaceutski prihvatljive soli. where R represents hydrogen, an alkyl group or COR15; R 1 , R 2 , R 11 and R 12 are independently selected from hydrogen or lower alkyl groups; R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, hydroxy, halogen, lower alkyl groups, lower alkoxy groups, mono- or di-lower alkylamino groups, NH 2 or NR 13 COR 14 ; R 7 , R 8 , R 9 and R 10 are independently selected from hydrogen, hydroxy, lower alkyl groups, lower alkoxy groups, mono- or di-lower alkylamino groups, NH 2 or NR 13 COR 14 ; R 13 , R 14 are independently selected from hydrogen or lower alkyl groups, provided that, when R represents COR 15 , then at least one of R 3 to R 10 represents hydroxy or mono- or di-lower alkylamino; and their enantiomers and pharmaceutically acceptable salts.

Indenolske i izo-indenolske strukture iz sadašnjeg izuma imaju slijedeću numeraciju u prstenovima: The indenol and iso-indenol structures of the present invention have the following ring numbering:

INDENOINDOLOVA STRUKTURA INDENOINDOLE STRUCTURE

[image] [image]

4b, 5, 9b, 10-Tetrahidroindeno(1,2-b) indol (IHII) 4b, 5, 9b, 10-Tetrahydroindeno(1,2-b) indole (IHII)

IZO-INDENOINDOLOVA STRUKTURA ISO-INDENOINDOLE STRUCTURE

[image] [image]

5, 5A, 10b-Tetrahidroindeno(2,1-b) indol (izo-THII) 5, 5A, 10b-Tetrahydroindeno(2,1-b) indole (iso-THII)

Alkil grupa u definiciji R predstavlja alkil grupu sa 1-24 ugljikova atoma, metil, etil, n-propil, izo-propil, n-butil, sec-butil, terc-butil, pentil, heksadecil, oktadecil. The alkyl group in the definition of R represents an alkyl group with 1-24 carbon atoms, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexadecyl, octadecyl.

Izraz “niži” u definiciji supstituenata u spojevima iz sadašnjeg izuma podrazumijeva broj ugljikovih atoma koji nije veći od 6, a poželjno nije veći od 4. The term "lower" in the definition of substituents in the compounds of the present invention implies a number of carbon atoms that is not greater than 6, and preferably not greater than 4.

Niže alkil grupe u definicijama za R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 i R15, su alkil grupe sa 1-6 ugljikovih atoma, poželjno 1-4 ugljikova atoma, npr. metil etil, n-propil, izopropil, n-butil, sec-butil i terc-butil, pri čemu su poželjne metil i etil. Lower alkyl groups in the definitions for R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and R15 are alkyl groups with 1-6 carbon atoms, preferably 1-4 carbon atoms, eg methyl ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl, with methyl and ethyl being preferred.

Niže alkoksi grupe u definicijama za R3, R4, R5, i R6, R7, R8, R9 i R10 su grupe s 1-6 ugljikovih atoma, poželjno 1-4 atoma, npr. metoksi, etoksi, n-propoksi, izo-propoksi, n-butoksi, sec-butoksi ili terc-butoksi, pri čemu su povoljne metoksi i etoksi. Lower alkoxy groups in the definitions for R3, R4, R5, and R6, R7, R8, R9 and R10 are groups with 1-6 carbon atoms, preferably 1-4 atoms, e.g. methoxy, ethoxy, n-propoxy, iso-propoxy , n-butoxy, sec-butoxy or tert-butoxy, with methoxy and ethoxy being preferred.

Halogen u definiciji R3, R4, R5 ili R6 predstavlja klor, brom, jod ili fluor. Halogen in the definition of R3, R4, R5 or R6 represents chlorine, bromine, iodine or fluorine.

Mono- ii di-niže alkilamino grupe u definiciji za R3, R4, R5, R6, R7, R8, R9 i R10 uključuju metilamino, dimetilamino, etilamino, dietilamino, propilamino, dipropilamino, butilamino, dibutilamino, pri čemu su poželjne etilamino i dietilamino. Mono- and di-lower alkylamino groups in the definition for R3, R4, R5, R6, R7, R8, R9 and R10 include methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dipropylamino, butylamino, dibutylamino, with ethylamino and diethylamino being preferred. .

Poželjni spojevi iz sadašnjeg izuma su oni u kojima R, R1, R2, R4, R6 i R10 predstavljaj vodike, a R5 i/ili R8 su niže alkoksi grupe, naročito metoksi, i/ili R3, R5, R7, R9, i/ili R12 predstavljaju niže alkil grupe, naročito metil, etil, izopropil, i spojevi u kojima su R5 i/ili R8 mono- ili di-alkilamino grupe, naročito etilamino i/ili dietiamino. Preferred compounds from the present invention are those in which R, R1, R2, R4, R6 and R10 represent hydrogen, and R5 and/or R8 are lower alkoxy groups, especially methoxy, and/or R3, R5, R7, R9, and/or or R12 represent lower alkyl groups, especially methyl, ethyl, isopropyl, and compounds in which R5 and/or R8 are mono- or di-alkylamino groups, especially ethylamino and/or diethylamino.

Primjena tetrahidroindenoindolovih spojeva formula IA i IB, uključenih u sadašnji izum, su slijedeći: Applications of the tetrahydroindenoindole compounds of formulas IA and IB, included in the present invention, are as follows:

cis-4b,5,9b-10-tetrahidroindeno[1,2-b]indol cis-4b,5,9b-10-tetrahydroindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-6,8-dimetilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-6,8-dimethylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-5,8-dimetilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-5,8-dimethylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-8-metilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-8-methylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-4b,6,8,9b-tetrametilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-4b,6,8,9b-tetramethylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-8-izopropilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-8-isopropylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-8-metoksi-5-metilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-8-methoxy-5-methylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-8-metoksiindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-8-methoxyindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-10,10-dimetilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-10,10-dimethylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-9b-metilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-9b-methylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-4b-9b-dimetilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-4b-9b-dimethylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-2-metoksi-1,3-dimetilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-2-methoxy-1,3-dimethylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-2-metoksi-1,3-dimetil-8-izopropilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-2-methoxy-1,3-dimethyl-8-isopropylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-4b-metilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-4b-methylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-2-hidroksi-1,3-dimetil-8-izopropilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-2-hydroxy-1,3-dimethyl-8-isopropylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-2-hidroksi-1,3-dimetilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-2-hydroxy-1,3-dimethylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-4b-8,9b-trimetilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-4b-8,9b-trimethylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-8-izopropil-4b,9b-dimetilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-8-isopropyl-4b,9b-dimethylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-8-izopropil-4b-metilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-8-isopropyl-4b-methylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-2,8-dimetoksi-1,3-dimetilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-2,8-dimethoxy-1,3-dimethylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-4b,5,8,9b-tetranetilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-4b,5,8,9b-tetraethylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-8-terc-butilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-8-tert-butylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-8-metoksi-7,9-dimetilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-8-methoxy-7,9-dimethylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-8-metoksi-6-metilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-8-methoxy-6-methylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-8-dietilamino-5-etilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-8-diethylamino-5-ethylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-2-dietilaminoindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-2-diethylaminoindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-8-terc-butil-4b-metilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-8-tert-butyl-4b-methylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-8-fluoroindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-8-fluoroindeno[1,2-b]indole

cis-5,5a,6,10b,10-tetrahidroindeno[1,2-b]indol cis-5,5a,6,10b,10-tetrahydroindeno[1,2-b]indole

cis-5,5a,10b,10-tetrahidro-9-metoksiindeno[1,2-b]indol cis-5,5a,10b,10-tetrahydro-9-methoxyindeno[1,2-b]indole

cis-5,5a,10b,10-tetrahidro-9-izopropilindeno[1,2-b]indol cis-5,5a,10b,10-tetrahydro-9-isopropylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-8-metoksi-4b,6-dimetilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-8-methoxy-4b,6-dimethylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-8-metoksi-4b,5,6-trimetilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-8-methoxy-4b,5,6-trimethylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-8-metoksi-5,6-dimetilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-8-methoxy-5,6-dimethylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-8-metoksi-6-izopropilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-8-methoxy-6-isopropylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-8-metoksi-4b-metil-6-izopropilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-8-methoxy-4b-methyl-6-isopropylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-8-metoksi-4,6-dimetilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-8-methoxy-4,6-dimethylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-8-metoksi-4,4b,6-trimetilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-8-methoxy-4,4b,6-trimethylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-4b-5,8,9b-pentametilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-4b-5,8,9b-pentamethylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-8-dietilamino-6-metilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-8-diethylamino-6-methylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-8-dietilamino-4b-6-dimetiliindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-8-diethylamino-4b-6-dimethylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-8-dietilamino-4b-5,6-trimetilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-8-diethylamino-4b-5,6-trimethylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-8-metoksi-6,10,10-trimetilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-8-methoxy-6,10,10-trimethylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-8-metoksi-4b,6,10,10-tetrametilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-8-methoxy-4b,6,10,10-tetramethylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-8-dietilamino-6,10,10-trimetilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-8-diethylamino-6,10,10-trimethylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-8-dietilamino-4B,6,10,10-tetrametilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-8-diethylamino-4B,6,10,10-tetramethylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-8-hidroksi-7,9-dimetilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-8-hydroxy-7,9-dimethylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-8-hidroksi-4b,7,9-trimetilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-8-hydroxy-4b,7,9-trimethylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-8-hidriksi-7,9-diterc-butilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-8-hydroxy-7,9-di-tert-butylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-8-hidroksi-6,7,9-trimetilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-8-hydroxy-6,7,9-trimethylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-8-hidroksi-4b,6,7,9-tetrametilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-8-hydroxy-4b,6,7,9-tetramethylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-8-metoksi-4b,6,9b-trimetilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-8-methoxy-4b,6,9b-trimethylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-8-metoksi-4b,5,6,9b-tetrametilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-8-methoxy-4b,5,6,9b-tetramethylindeno[1,2-b]indole

cis-4b,5,9b,10-tetrahidro-8-dietilamino-4b,6,9b-trimetilindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-8-diethylamino-4b,6,9b-trimethylindeno[1,2-b]indole

cis-5,5a,6,10b-tetrahidro-9-metoksi-7-metilindeno[2,1-b]indol cis-5,5a,6,10b-tetrahydro-9-methoxy-7-methylindeno[2,1-b]indole

cis-5,5a,6,10b-tetrahidro-9-metoksi-5a,7-dimetilindeno[2,1-b]indol cis-5,5a,6,10b-tetrahydro-9-methoxy-5a,7-dimethylindeno[2,1-b]indole

cis-5,5a,6,10b-tetrahidro-9-dietilamino-7-metilindeno[2,1-b]indol cis-5,5a,6,10b-tetrahydro-9-diethylamino-7-methylindeno[2,1-b]indole

cis-5,5a,6,10b-tetrahidro-9-dietilamino-5a,7-dimetilindeno[2,1-b]indol cis-5,5a,6,10b-tetrahydro-9-diethylamino-5a,7-dimethylindeno[2,1-b]indole

cis-5,5a,6,10b-tetrahidro-9-hidroksi-8,10-dimetilindeno[2,1-b]indol cis-5,5a,6,10b-tetrahydro-9-hydroxy-8,10-dimethylindeno[2,1-b]indole

cis-5,5a,6,10b-tetrahidro-9-hidroksi-7,8,10-trimetilindeno[2,1-b]indol cis-5,5a,6,10b-tetrahydro-9-hydroxy-7,8,10-trimethylindeno[2,1-b]indole

cis-5,5a,6,10b-tetrahidro-9-hidroksi-5a,7,8,10-tetrametilindeno[2,1-b]indol cis-5,5a,6,10b-tetrahydro-9-hydroxy-5a,7,8,10-tetramethylindeno[2,1-b]indole

cis-4b,5,9b,10-tetrahidro-6-izopropilindeno[2,1-b]indol cis-4b,5,9b,10-tetrahydro-6-isopropylindeno[2,1-b]indole

cis-5,5a,6,10b-tetrahidro-9-metoksi-5,5,7-trimetilindeno[2,1-b]indol cis-5,5a,6,10b-tetrahydro-9-methoxy-5,5,7-trimethylindeno[2,1-b]indole

cis-5,5a,6,10b-tetrahidro-9-dietilamino-5,5,7-trimetilindeno[2,1-b]indol cis-5,5a,6,10b-tetrahydro-9-diethylamino-5,5,7-trimethylindeno[2,1-b]indole

cis-4b,5,9b,10b-tetrahidro-2-dietilamino-8-metoksi-6-metilindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-2-diethylamino-8-methoxy-6-methylindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro-8-metoksi-4b-izopropilindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-8-methoxy-4b-isopropylindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro-8-metoksi-4b-izopropil-6-metilindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-8-methoxy-4b-isopropyl-6-methylindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro-8-izopropil-5-metilindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-8-isopropyl-5-methylindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro-8-metoksi-6-etilindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-8-methoxy-6-ethylindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro-3-metoksi-4b-metilindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-3-methoxy-4b-methylindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro-7-metoksi-4b-metilindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-7-methoxy-4b-methylindeno[1,2-b]indole

cis-5,5a,6,10b-tetrahidro-3-hidroksi-2,4-dimetilindeno[2,1-b]indol cis-5,5a,6,10b-tetrahydro-3-hydroxy-2,4-dimethylindeno[2,1-b]indole

cis-4b,5,9b,10b-tetrahidro-8-acetamido-6-metilindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-8-acetamido-6-methylindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro-2-acetamido-8-metoksi-6-metilindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-2-acetamido-8-methoxy-6-methylindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro-8-terc-butil-5-metilindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-8-tert-butyl-5-methylindeno[1,2-b]indole

cis-5,5a,6,10b-tetrahidro-3-acetamidoindeno[2,1-b]indol cis-5,5a,6,10b-tetrahydro-3-acetamidoindeno[2,1-b]indole

cis-4b,5,9b,10b-tetrahidro-2-acetamidoindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-2-acetamidoindeno[1,2-b]indole

cis-5,5a,6,10b-tetrahidro-6-metilindeno[2,1-b]indol cis-5,5a,6,10b-tetrahydro-6-methylindeno[2,1-b]indole

cis-5,5a,6,10b-tetrahidro-6-etil-9-izopropilindeno[2,1-b]indol cis-5,5a,6,10b-tetrahydro-6-ethyl-9-isopropylindeno[2,1-b]indole

cis-5,5a,6,10b-tetrahidro-9-fluoroindeno[2,1-b]indol cis-5,5a,6,10b-tetrahydro-9-fluoroindeno[2,1-b]indole

cis-5,5a,6,10b-tetrahidro-9-terc-butilindeno[2,1-b]indol cis-5,5a,6,10b-tetrahydro-9-tert-butylindeno[2,1-b]indole

Poželjni spojevi iz sadašnjeg izuma, koji posjeduju antioksidantna svojstva, su slijedeća: Preferred compounds of the present invention, which possess antioxidant properties, are as follows:

cis-4b,5,9b,10b-tetrahidroindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydroindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro-6,8-dimetilindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-6,8-dimethylindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro-5,8-dimetilindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-5,8-dimethylindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro-8-metilindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-8-methylindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro-4b,6,8,9b-tetrametilindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-4b,6,8,9b-tetramethylindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro-8-izopropilindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-8-isopropylindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro-8-metoksi-5-metilindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-8-methoxy-5-methylindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro-8-metoksiindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-8-methoxyindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro-10,10-dimetilindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-10,10-dimethylindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro-9b-metilindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-9b-methylindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro-4b,9b-dimetilindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-4b,9b-dimethylindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro-4b,5,9b-trimetilindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-4b,5,9b-trimethylindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro-2-metoksi-1,3-dimetilindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-2-methoxy-1,3-dimethylindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro-2-metoksi-1,3-dimetil-8-izopropilindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-2-methoxy-1,3-dimethyl-8-isopropylindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro-4b-metilindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-4b-methylindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro-2-hidroksi-1,3-dimetil-8-izopropilindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-2-hydroxy-1,3-dimethyl-8-isopropylindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro-2-hidroksi-1,3-demetilindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-2-hydroxy-1,3-demethylindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro-4b,8,9b-trimetilindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-4b,8,9b-trimethylindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro-8-izopropil-4b,9b-dimetilindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-8-isopropyl-4b,9b-dimethylindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro-8-izopropil-4b-metilindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-8-isopropyl-4b-methylindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro-2,8-dimetoksi-1,3-dimetilindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-2,8-dimethoxy-1,3-dimethylindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro-4b,5,8,9b-tetrametilindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-4b,5,8,9b-tetramethylindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro-8-terc-butilindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-8-tert-butylindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro-8-metoksi-7,9-dimetilindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-8-methoxy-7,9-dimethylindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro-8-metoksi-6-metilindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-8-methoxy-6-methylindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro--dietilamino-5-etilindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro--diethylamino-5-ethylindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro-2-dietilaminoindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-2-diethylaminoindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro--terc-butil-4b-metilindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-tert-butyl-4b-methylindeno[1,2-b]indole

cis-4b,5,9b,10b-tetrahidro-8-fluoroindeno[1,2-b]indol cis-4b,5,9b,10b-tetrahydro-8-fluoroindeno[1,2-b]indole

cis-5,5a,6,10b-tetrahidroindeno[2,1-b]indeno cis-5,5a,6,10b-tetrahydroindeno[2,1-b]indeno

cis-5,5a,6,10b-tetrahidro-9-metoksiindeno[2,1-b]indeno cis-5,5a,6,10b-tetrahydro-9-methoxyindeno[2,1-b]indeno

cis-5,5a,6,10b-tetrahidro-9-izopropilindeno[2,1-b]indeno cis-5,5a,6,10b-tetrahydro-9-isopropylindeno[2,1-b]indeno

Spojevi sa formulama IA i IB mogu se javiti ili kao takvi, ili u obliku farmaceutski prihvatljivih soli. Compounds of formulas IA and IB can occur either as such or in the form of pharmaceutically acceptable salts.

Za spojeve općih formula IA i IB koji su asimetrični, u opseg sadašnjeg izuma ulaze kako čisti enentiomeri, tako i smjese enentiomera i racemske smjese. For compounds of the general formulas IA and IB which are asymmetric, the scope of the present invention includes both pure enantiomers, as well as mixtures of enantiomers and racemic mixtures.

Farmaceutski preparati Pharmaceutical preparations

Spojevi formule IA i IB normalno će se davati oralno, rektalno, dermalno ili injekcijom, u obliku farmaceutskih preparata koji se sastoje od aktivnog sastojka, bilo u obliku slobodne baze ili kao netoksične farmaceutski prihvatljive adicijske soli sa kiselinom, npr. klorohidrata, bromohidrata, laktata, acetata, fosfata, sulfata, sulfamata, citrata, tartarata, oksalata i slično u farmaceutski prihvatljivom doznom obliku. Dozni oblik može predstavljati kruti, polukruti ili tekući preparat. Aktivna supstancija će, u načelu, sačinjavati od 0.1 do 99 mas. posto preparata, bliže od 0.5 do 20 mas. posto za preparate namijenjene davanju injekcijom i između 0.2 do 50 mas. posto za preparate koji su pogodni za oralno davanje. Dermalno davanje bi, obično, uključivalo 0.1 do 5 mas.posto aktivnog sastojka u pogodnom nosaču. Compounds of formula IA and IB will normally be administered orally, rectally, dermally or by injection, in the form of pharmaceutical preparations consisting of the active ingredient, either in the form of a free base or as a non-toxic pharmaceutically acceptable addition salt with an acid, e.g., chlorohydrate, bromohydrate, lactate , acetate, phosphate, sulfate, sulfamate, citrate, tartrate, oxalate and the like in a pharmaceutically acceptable dosage form. The dosage form can be a solid, semi-solid or liquid preparation. The active substance will, in principle, comprise from 0.1 to 99 wt. percent of the preparation, closer to 0.5 to 20 wt. percent for preparations intended for injection and between 0.2 and 50 wt. percent for preparations that are suitable for oral administration. Dermal administration would typically include 0.1 to 5 weight percent of the active ingredient in a suitable carrier.

Za dobivanje farmaceutskih preparata koji sadrže spoj formule I u obliku doznih jedinica za oralno davanje, odabrani spoj može se miješati sa čvrstim ekscipijentom, npr. laktozom, saharozom, sorbitolom, manitolom, škrobovima kao što je krumpirov škrob, kukuruzni škrob ili amilopektin, derivatima celuloze, veznim tvarima kao što su želatina ili polivinilpirolidon, i sredstvima za podmazivanje kao što su magnezijev stearat, kalcijev stearat, polietilen glikol, voskovi, parafin i slično, te da se zatim komprimira u tablete. To obtain pharmaceutical preparations containing the compound of formula I in the form of dosage units for oral administration, the selected compound can be mixed with a solid excipient, for example lactose, sucrose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives , binders such as gelatin or polyvinylpyrrolidone, and lubricants such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then compressed into tablets.

Ukoliko su potrebne prevučene tablete, jezgra, pripremljena kao što je opisano gore, mogu se prevući sa koncentriranom otopinom šećera koji, na primjer, može sadržavati gumiarabiku, želatinu, talk, titan dioksid i slično. Alternativno, tableta se može presvući s polimerima koji su poznati stručnjacima, otopljenim u isparivoj organskoj otopini ili smjesi organskih otapala. Ovim prevlakama mogu se dodati obojene tvari, kao bi se lakše razlikovale tablete koje sadrže različite aktivne supstancije ili različite količine aktivnih spojeva. If coated tablets are required, the core, prepared as described above, can be coated with a concentrated sugar solution which, for example, may contain gum arabic, gelatin, talc, titanium dioxide and the like. Alternatively, the tablet can be coated with polymers known to those skilled in the art, dissolved in a volatile organic solution or mixture of organic solvents. Colored substances can be added to these coatings, in order to more easily distinguish tablets containing different active substances or different amounts of active compounds.

Za dobivanje mekih želatinskih kapsula, aktivna supstancija može se miješati sa npr. biljnim uljem ili polietilen glikolom. To obtain soft gelatin capsules, the active substance can be mixed with, for example, vegetable oil or polyethylene glycol.

Tablete od tvrde želatine mogu sadržavati granule aktivne supstancije, uz korištenje navedenih ekscipijenata za tablete, npr. laktoze, saharoze, sorbitola, manitola, škrobova (npr. krumpirovog škroba, kukuruznog škroba ili amilopektina), celuloznih derivata ili želatina. U kapsule od tvrde želatine mogu se puniti i tekući ili polukruti oblici lijeka. Tablets made of hard gelatin may contain granules of the active substance, with the use of the indicated excipients for tablets, eg lactose, sucrose, sorbitol, mannitol, starches (eg potato starch, corn starch or amylopectin), cellulose derivatives or gelatin. Hard gelatin capsules can be filled with liquid or semi-solid forms of medicine.

Jedinične doze za rektalnu primjenu mogu predstavljati otopine ili suspenzije, ili se mogu pripremiti u obliku suspozitorija koji sadrže aktivnu suspstanciju u smjesi s neutralnom masnom bazom, ili želatinske rektalne kapsule koje sadrže aktivnu supstanciju u smjesi sa biljnim ili parafinskim uljem. Unit doses for rectal administration can be solutions or suspensions, or they can be prepared in the form of suppositories containing the active substance in a mixture with a neutral fatty base, or gelatin rectal capsules containing the active substance in a mixture with vegetable or paraffin oil.

Tekući preparati za oralnu primjenu mogu biti u obliku sirupa ili suspenzija, na primjer otopina koje sadrže od oko 0.2 do oko 20 mas. posto ovdje opisane aktivne supstancije, dok je ostatak šećer i smjesa etanola, vode, glicerina i propilen glikola. Po potrebi ovakvi tekući preparati mogu sadržavati i sredstva za bojenje, ukus i miris, saharin i karboksimetil celulozu kao sredstvo za davanje gustine, ili druge ekscipijente koji su poznati stručnjacima. Liquid preparations for oral administration can be in the form of syrups or suspensions, for example solutions containing from about 0.2 to about 20 wt. percent of the active substance described here, while the rest is sugar and a mixture of ethanol, water, glycerin and propylene glycol. If necessary, such liquid preparations can also contain agents for coloring, taste and smell, saccharin and carboxymethyl cellulose as a thickening agent, or other excipients known to experts.

Otopine za parenteralno davanje injekcijom mogu se dobiti u vodenoj otopini farmaceutski prihvatljive, u vodi otopljene soli aktivnog spoja, poželjno u koncentraciji od oko 0.5 do oko 10 mas. %. Ove otopine mogu sadržavati i stabilizatore i/ili puferska sredstva i mogu se puniti u ampule koje sadrže različite doze. Solutions for parenteral administration by injection can be obtained in an aqueous solution of a pharmaceutically acceptable, water-dissolved salt of the active compound, preferably in a concentration of about 0.5 to about 10 wt. %. These solutions may also contain stabilizers and/or buffering agents and may be filled into ampoules containing different doses.

Pogodne dnevne doze spojeva iz izuma u terapeutskom tretmanu ljudi kreću se oko 0.01 do 100 mg/kg tjelesne težine za oralno davanje i od 0.001 do 100 mg/kg tjelesne težine za parenteralno davanje. Suitable daily doses of the compounds of the invention in the therapeutic treatment of humans range from about 0.01 to 100 mg/kg of body weight for oral administration and from 0.001 to 100 mg/kg of body weight for parenteral administration.

Postupak za dobivanje Procedure for obtaining

Spojevi iz izuma mogu se pripremiti kao što je opisano u daljnjem tekstu. Međutim, izum nije ograničen na ove postupke, već se spojevi mogu dobiti i postupcima koji su već opisani u znanosti. The compounds of the invention can be prepared as described below. However, the invention is not limited to these procedures, but the compounds can also be obtained by procedures that have already been described in science.

Postupci u kojima se THII i izo-THII spojevi dobivaju iz materijala koji ne sadrže THII niti izo-THII. Processes in which THII and iso-THII compounds are obtained from materials that do not contain THII or iso-THII.

a. 4b,5,9b,10-Tetrahidroindeno[1,2-b]indol (THII, IA) i analozi koji sadrže funkcionalne grupe na atomima benzoloidnih prstena i/ili radikale na C-10 kao što su niži alkil, niži alkoksi, mogu se dobiti redukcijom odgovarajućeg 5,10-dihidroindeno[1,2-b]idola (DHII): a. 4b,5,9b,10-Tetrahydroindeno[1,2-b]indole (THII, IA) and analogs containing functional groups on benzoloid ring atoms and/or radicals at C-10 such as lower alkyl, lower alkoxy , can be obtained by reduction of the corresponding 5,10-dihydroindeno[1,2-b]idol (DHII):

[image] [image]

R, R1, R2, R3, R4, R5, R6, R7, R8, R9 i R10 su kao što je definirano kod formule IA. R, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are as defined in formula IA.

DHII ili analozi se reduciraju reakcijom s cinkom i vodenom otopinom mineralne kiseline, kao što je klorovodikova kiselina, ili još efikasnije reakcijom s redukcijskim sredstvom na bazi bora, kao što je natrijev cijanoborohidrid u nekom otapalu, često u octenoj kiselini ili BH3 u tetrahidrofuranu. Alternativno se može koristiti morfolino boran u nekom otapalu, često u tetrahidrofuranu ili dioksanu, u prisutnosti jake kiseline, npr. klorovodikove kiseline. Još jedna mogućnost je da se koristi trialkilsilan. Na kraju reakcije, proizvod se izolira razblaživanjem reakcijske smjese vodom, neutralizacijom, te zatim ili filtriranjem ili ekstrakcijom sa otapalom. Redukcija se alternativno postiže hidrogeniranjem preko katalizatora kao što je paladij, u ovom slučaju se spoj DHII otapa u pogodnom otapalu npr. etanolu, octenoj kiselini ili etil acetatu. u ovom slučaju proizvod se izolira uklanjanjem katalizatora i isparavanjem otapala pod smanjenim tlakom. THII i njegovi analozi mogu se prečistiti kristalizacijom iz pogodnog otapala, ili kromatografijom na koloni silikagela. DHII i njegovi analozi sintetiziraju se Fisherovom reakcijom indolizacije iz fenilhidrazina formule II i 1-indanona formule III, gdje je R11 vodik. 5-Alkil-4b,5,9b,10-tetrahidroindeno[1,2-b]indoli (N-Alkil THII) dobivaju se ili N-alkiliranjem odgovarajućih DHII spojeva prije redukcije, ili iz odgovarajućih 5H-THII spojeva direktnim N-alkiliranjem. U oba slučaja poželjno je da se grade intermedijerni anioni tetracikličnih amina, njihovim tretiranjem sa bazom prije reakcije s alkil halogenidom ili alkil sulfatom. DHII or analogs are reduced by reaction with zinc and an aqueous solution of a mineral acid, such as hydrochloric acid, or more efficiently by reaction with a boron-based reducing agent, such as sodium cyanoborohydride in some solvent, often acetic acid or BH3 in tetrahydrofuran. Alternatively, morpholino borane can be used in a solvent, often tetrahydrofuran or dioxane, in the presence of a strong acid, eg hydrochloric acid. Another possibility is to use trialkylsilane. At the end of the reaction, the product is isolated by diluting the reaction mixture with water, neutralization, and then either filtration or solvent extraction. The reduction is alternatively achieved by hydrogenation over a catalyst such as palladium, in this case the compound DHII is dissolved in a suitable solvent eg ethanol, acetic acid or ethyl acetate. in this case the product is isolated by removing the catalyst and evaporating the solvent under reduced pressure. THII and its analogs can be purified by crystallization from a suitable solvent, or by chromatography on a silica gel column. DHII and its analogs are synthesized by Fisher's indolization reaction from phenylhydrazine of formula II and 1-indanone of formula III, where R11 is hydrogen. 5-Alkyl-4b,5,9b,10-tetrahydroindeno[1,2-b]indoles (N-Alkyl THII) are obtained either by N-alkylation of the corresponding DHII compounds before reduction, or from the corresponding 5H-THII compounds by direct N-alkylation . In both cases, it is preferable to build intermediate anions of tetracyclic amines by treating them with a base before reacting with an alkyl halide or alkyl sulfate.

b. 4b,5,9b,10-tetrahidroindeno[1,2-b]indol i analozi koji imaju supstituient na C-9b mogu se sintetizirati Fischer-ovom indolizacijom nakon koje slijedi redukcija intermedijernih indolenina (IV): b. 4b,5,9b,10-tetrahydroindeno[1,2-b]indole and analogues having a substituent at C-9b can be synthesized by Fischer indolization followed by reduction of intermediate indolenines (IV):

[image] [image]

gdje su R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 i R11 kao što je definirano kod formule IA, poslije čega se, ukoliko je potrebno, vrši N-alkiliranje sa R-halogenidom ili R-sulfatom, gdje je R kao što je definirano kod formule IA. where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are as defined in formula IA, after which, if necessary, N-alkylation with R-halide or R- sulfate, where R is as defined by formula IA.

2-Supstituirani-1-indanoni (III) ili ekvivalentne polazne tvari, sa pogodnim funkcionalnim grupama supstituiranim u benzoloidovom prstenu i na C-3, mogu reagirati s fenilhidrazinima (II) bilo u obliku slobodne baze ili kao soli, često kao klorohidrati. Normalno se reagensi otapaju u nekom otapalu, poželjno u alkoholnom otapalu kao što su etanol ili propanol. U nekim slučajevima nije potrebno dodavanje topline, dok je u drugima potrebno zagrijavati reakcijsku smjesu na refluksu 1 sat ili duže. Fenilhidrazonski proizvod može se izolirati razblaživanjem reakcijske smjese vodom i odvojiti se filtriranjem ili ekstrakcijom sa pogodnim otapalom. Daljnje prečišćavanje postiže se kristalizacijom ili kromatografijom. U zadnjem slučaju pogodna je kromatografija na koloni silikagela, a kao eluent može se koristiti čitav niz otapala. 2-Substituted-1-indanones (III) or equivalent starting materials, with suitable functional groups substituted in the benzolide ring and at C-3, can react with phenylhydrazines (II) either in free base form or as salts, often as chlorohydrates. Normally, the reagents are dissolved in some solvent, preferably an alcoholic solvent such as ethanol or propanol. In some cases it is not necessary to add heat, while in others it is necessary to heat the reaction mixture at reflux for 1 hour or longer. The phenylhydrazone product can be isolated by diluting the reaction mixture with water and separated by filtration or extraction with a suitable solvent. Further purification is achieved by crystallization or chromatography. In the latter case, chromatography on a silica gel column is suitable, and a whole range of solvents can be used as an eluent.

Ciklizacija fenilhidrazona u indolenine (IV) se postiže ponovnim otapanjem u pogodnom otapalu, poželjno alkoholu kao što je etanol ili propanol, i tretiranjem otopine s kiselinom, npr. klorovodikovom, octenom ili trifluorooctenom kiselinom. Cyclization of phenylhydrazones to indolenines (IV) is achieved by redissolving in a suitable solvent, preferably an alcohol such as ethanol or propanol, and treating the solution with an acid, eg hydrochloric, acetic or trifluoroacetic acid.

Toplota može, ali i ne mora biti potrebna. Također se mogu koristiti i drugi reagensi za cirkulaciju uključujući Lewis-ove kiseline kao što je cink klorid, ili reagenske koji sadrže atom fosfora, na primjer fosfor triklorid, fosfor oksitriklorid, polifosforna kiselina ili polifosfonati. Heat may or may not be required. Other cyclization reagents may also be used including Lewis acids such as zinc chloride, or reagents containing a phosphorus atom, for example phosphorus trichloride, phosphorus oxytrichloride, polyphosphoric acid or polyphosphonates.

Ukoliko se umjesto fenilhidrazina, u reakcijama sa indanonima, koriste njihove soli, onda se ciklizacija intermedijernih fenilhidrazona u indolenine može javiti i spontano. If instead of phenylhydrazine, in the reactions with indanones, their salts are used, then the cyclization of intermediate phenylhydrazones into indolenines can also occur spontaneously.

U nekim slučajevima je primjećeno da fenilhidrazoni dobiveni reakcijom fenilhidrazina na 2-supstituiranim-1-indanonima, uz zagriajvanje u otapalu visoke točke vrenja kao što je dietilen glikol, daju odgovarajuće derivate THII. In some cases, it has been observed that phenylhydrazones obtained by the reaction of phenylhydrazine on 2-substituted-1-indanones, upon heating in a high-boiling solvent such as diethylene glycol, give the corresponding THII derivatives.

Redukcija indolenina (IV) do derivata THII (V) koji su supstituirani na C-9b, postiže se uz korištenje standardnih redukcijskih sredstava kao što je natrijev borohidrid, u pogodnom otapalu kao što je etanol. Proizvodi se zatim izoliraju i prečišćavaju na uobičajeni način. Reduction of indolenine (IV) to THII (V) derivatives which are substituted at C-9b is achieved using standard reducing agents such as sodium borohydride in a suitable solvent such as ethanol. The products are then isolated and purified in the usual way.

c. 4b,9b-Dialkil-4b,5,9b,10-tetrahidroindeno[1,2-b]indoli (IV) i njihovi analozi mogu se dobiti direktno reakcijom indolenina (IV) sa litij alkilima (R12Li) u aprotičnom otapalu kao što je bezvodni tetrahidrofuran. c. 4b,9b-Dialkyl-4b,5,9b,10-tetrahydroindeno[1,2-b]indoles (IV) and their analogues can be obtained directly by reacting indolenine (IV) with lithium alkyls (R12Li) in an aprotic solvent such as anhydrous tetrahydrofuran.

[image] [image]

gdje su R1 do R12 kao što je definirani kod formule IA. Nakon toga, po potrebi, slijedi N-alkiliranje sa R-halogenidom ili R-sulfatom, gdje je R kao što je definirano kod formule IA. where R 1 to R 12 are as defined by formula IA. This is followed, if necessary, by N-alkylation with R-halide or R-sulfate, where R is as defined in formula IA.

d. 5,5a,6,10b-tetrahidroindeno[2,1-b]indol (izo-THII) i analozi mogu se dobiti redukcijom odgovarajućeg 5,6-dihidroindeno [2,1-b]indola (izo-DHII) na isti način kao što je navedeno u gornjoj metodi pod a. d. 5,5a,6,10b-tetrahydroindeno[2,1-b]indole (iso-THII) and analogues can be obtained by reducing the corresponding 5,6-dihydroindeno[2,1-b]indole (iso-DHII) to the same way as mentioned in the above method under a.

e. 10b-Supstituirani-5,5a,6,10b-tetrahidroindeno[2,1-b]indoli (IX) i analozi mogu se sintetizirati iz indan-2-ona (XII) koji imaju supstituent na C-3, njihovom reakcijom sa pogodnim fenilhidrazinima (II) pod istim uvjetima kao što je opisano za dobivanje indolenina (IV). Intermedijerni proizvodi su odgovarajući indolenini (VIII) koji, kada se otope u pogodnom otapalu, često etanolu, i reagiraju sa redukcijskim sredstvom, kao što je natrijev borohidrid, daju izo-THII spojevi (IX) sa alkil supstituentom u položaju 10b. Ovi spojevi mogu se izolirati ekstrakcijom sa pogodnim otapalom. e. 10b-Substituted-5,5a,6,10b-tetrahydroindeno[2,1-b]indoles (IX) and analogues can be synthesized from indan-2-ones (XII) having a substituent at C-3, by their reaction with suitable phenylhydrazines (II) under the same conditions as described for obtaining indolenines (IV). The intermediates are the corresponding indolenines (VIII) which, when dissolved in a suitable solvent, often ethanol, and reacted with a reducing agent, such as sodium borohydride, give the iso-THII compounds (IX) with an alkyl substituent in the 10b position. These compounds can be isolated by extraction with a suitable solvent.

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u formulama (VIII) i (IX) su R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 i R11 kao što je definirani kod formule IB. in formulas (VIII) and (IX) are R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 as defined by formula IB.

f. Izo-THII spojevi (X) koji imaju alkil supstituente na C-5a i C-10b se dobivaju iz odgovarajućih indolenina (VIII), preko reakcije sa alkil litijskim reagensom za 4b, 9b dialkilirane THII spojeve (VI). f. Iso-THII compounds (X) having alkyl substituents at C-5a and C-10b are obtained from the corresponding indolenines (VIII), via reaction with an alkyl lithium reagent for 4b, 9b dialkylated THII compounds (VI).

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pri čemu su R1 do R12 kao što je definirano kod formule IB. wherein R1 to R12 are as defined by formula IB.

Metode u kojima se THII ili izo-THII spojevi dobivaju Methods in which THII or iso-THII compounds are obtained

modifikacijom drugih THII ili ito-THII spojeva by modification of other THII or ito-THII compounds

g. 5-Alkil THII ili 6-alkil izo-THII derivati se dobivaju N-alkiliranjem odgovarajućih 5H-THII ili 6H-izo-THII spojeva otopljenih u aprotičnom otapalu, npr. acetonu, acetonitrilu, dimentilsulfoksidu (DMSO), dimentilformamidu (DMF), po potrebi i poželjno u prisustvu jake baze, npr. s natrij hidridom, pa se reakcijska smjesa zatim tretira sa alkil halogenidom ili alkil sulfatom. Alternativno, odgovarajući 5-alkil DHII ili 6-alkil izo-DHII može se reducirati reakcijom sa cinkom i vodenom otopinom mineralne kiseline kao što je klorovodikova kiselina, ili još efikasnije redukcijom sa redukcijskim sredstvom na bazi bora, kao što je natrij cijankoborohidrid i nekom otapalu, često octenoj kiselini ili BH3 u tetrahidrofuranu. Alternativno se može koristiti morfolino boran u nekom otapalu često tetrahidrofuranu ili dioksanu, u prisutnosti jake kiseline, npr. klorovodikove kiseline. Alternativno se također može koristiti trialkil silan. Na kraju reakcije proizvod se izolira razblaživanjem s vodom i zatim ili filtriranjem ili ekstrakcijom sa otapalom. Alternativno, redukcija se može vršiti hidrogeniranjem preko katalizatora kao što je paladijum, i u tom slučaju se 5-alkil-DHII ili 6-alkil-izo-DHII otapa u pogodnom otapalu, npr. etanolu, octenoj kiselini ili etil acetatu. U tom slučaju se proivzod izolira uklanjanjem katalizatora i isparavanjem otapala pod smanjenim tlakom. g. 5-Alkyl THII or 6-alkyl iso-THII derivatives are obtained by N-alkylation of the corresponding 5H-THII or 6H-iso-THII compounds dissolved in an aprotic solvent, e.g. acetone, acetonitrile, dimentylsulfoxide (DMSO), dimentylformamide (DMF) , if necessary and preferably in the presence of a strong base, for example with sodium hydride, so the reaction mixture is then treated with an alkyl halide or alkyl sulfate. Alternatively, the corresponding 5-alkyl DHII or 6-alkyl iso-DHII can be reduced by reaction with zinc and an aqueous solution of a mineral acid such as hydrochloric acid, or more efficiently by reduction with a boron-based reducing agent such as sodium cyanoborohydride and some solvent , often to acetic acid or BH3 in tetrahydrofuran. Alternatively, morpholino borane can be used in a solvent, often tetrahydrofuran or dioxane, in the presence of a strong acid, eg hydrochloric acid. Alternatively, trialkyl silane can also be used. At the end of the reaction, the product is isolated by dilution with water and then either by filtration or extraction with a solvent. Alternatively, the reduction can be carried out by hydrogenation over a catalyst such as palladium, in which case the 5-alkyl-DHII or 6-alkyl-iso-DHII is dissolved in a suitable solvent, eg ethanol, acetic acid or ethyl acetate. In this case, the product is isolated by removing the catalyst and evaporating the solvent under reduced pressure.

5-Alkil-THII ili 6-alkil-izo-THII spojevi mogu se prečistiti kristalizacijom iz pogodnog otapala ili kromatografijom na koloni silikagela. 5-Alkyl-THII or 6-alkyl-iso-THII compounds can be purified by crystallization from a suitable solvent or by silica gel column chromatography.

h. 5-Alkil THII ili 6-alkil izo-THII se sintetiziraju jednostavnom redukcijom odgovarajućih 5-aril ili 6-aril derivata uz korištenje standardnih metoda, npr. korištenjem litij aluminij hidrida. h. 5-Alkyl THII or 6-alkyl iso-THII are synthesized by simple reduction of the corresponding 5-aryl or 6-aryl derivatives using standard methods, eg using lithium aluminum hydride.

i. THII ili izo-THII spojevi se alkilamino grupama u R3-R6 i/ili R7-R10 mogu se dobiti iz odgovarajućih 5-acil THII ili 6-acil izo-THII nitro spojeva standardnim tehnikama redukcije, tj. korištenjem TiCl3/HCl, nakon čega slijedi jedno standardno N-alkiliranje i, po potrebi, kisela hidroliza 5- ili 6-acil grupa da bi se dobili 5- ili 6-nesupstituiranih spojeva. Korišteni nitro spojevi mogu se dobiti ili iz odgovarajućih DHII ili izo-DHII spojeva prema metodama pod a. ili pod d., ili preko nitriranja pogodno supstituiranih THII ili izo-THII spojeva. i. THII or iso-THII compounds with alkylamino groups in R3-R6 and/or R7-R10 can be obtained from the corresponding 5-acyl THII or 6-acyl iso-THII nitro compounds by standard reduction techniques, i.e. using TiCl3/HCl, followed by one standard N-alkylation and, if necessary, acid hydrolysis of the 5- or 6-acyl group to give the 5- or 6-unsubstituted compounds. The nitro compounds used can be obtained either from the corresponding DHII or iso-DHII compounds according to the methods under a. or under d., or through nitration of suitably substituted THII or iso-THII compounds.

j. Hidroksi supstituirani spojevi mogu se dobiti iz odgovarajućih alkoksi supstituiranih spojeva standardnim metodama dealkiliranja etera, npr. uz korištenje različitih Lewis-ovih kiselina. j. Hydroxy substituted compounds can be obtained from the corresponding alkoxy substituted compounds by standard ether dealkylation methods, for example with the use of various Lewis acids.

k. 4b-Alkil THII i izo-THII, tj. spojevi u kojima je R12 niža alkil grupa i R, R1 do R11 su kao što je definirano u formuli I, mogu se dobiti iz odgovarajućih 4b-nesupstituiranih analoga sekvencom metaliziranja, npr. uz korištenje butil litija, karbonizacije sa ugljen dioksidom, drugog usmjerenog metaliziranja, npr. uz korištenje butil litija, i alkiliranja sa R12-halogenidom ili R12-sulfatom, nakon čega slijedi konačna hidroliza dobivenog N-karboksiliranog intermedijera. k. 4b-Alkyl THII and iso-THII, i.e. compounds in which R12 is a lower alkyl group and R, R1 to R11 are as defined in formula I, can be obtained from the corresponding 4b-unsubstituted analogues by a metalation sequence, e.g. using butyl lithium, carbonization with carbon dioxide, other directed metalation, e.g. using butyl lithium, and alkylation with R12-halide or R12-sulfate, followed by final hydrolysis of the resulting N-carboxylated intermediate.

Postupci za dobivanje početnih materijala, kao što su 5,10-dihidroindeno-1,2-b indol (DHII) i 5,6-dihidroindeno 2,1-b indol i analoga koji sadrže funkcionalne grupe, opisani su u našoj neodlučenoj prijavi (zastupnikov broj 3961/2) koja je podnesena istog dana kao i sadašnja prijava. Procedures for obtaining starting materials, such as 5,10-dihydroindeno-1,2-b indole (DHII) and 5,6-dihydroindeno 2,1-b indole and analogs containing functional groups, are described in our pending application ( representative's number 3961/2) which was submitted on the same day as the current application.

U nastavku su dani primjeri koji ilustriraju principe i varijante izuma. Izum, međutim, nije ograničen samo na njih. Examples illustrating the principles and variants of the invention are given below. The invention, however, is not limited to them.

Sve temperature prikazane su u stupnjevima Celzija. All temperatures are shown in degrees Celsius.

Primjeri izvođenja Performance examples

Primjer 1 Example 1

cis-4b,5,9b,10-Tetrahidroindeno[1,2-b]indol cis-4b,5,9b,10-Tetrahydroindeno[1,2-b]indole

Suspenziji 5,10-dihidroindeno[1,2-b]indola (19.16 g, 93mmol) u glacijalnoj octenoj kiselini 300 cm3) dodavan je postupno, tokom pola sata, natrijev cijanoborohidrid (24 g, 400 mmol). Smjesa je miješana tokom 3 sata, dok se sav materijal nije otopio. Otopina je prosuta u ledenu vodu (500 cm3) i miješa 1 sat da bi se otopio borohidridni kompleks. Bistra otopina je zatim pažljivo neutralizirana s natrijevim hidroksidom, što je izazvalo stvaranje bijelog taloga. Talog je filtriran i ispran s vodom sve dok tekućina od ispiranja nije bila oslobođena cijanidnih iona. Sušenje je dalo naslovni spoj kao bijelu čvrstu supstanciju. Doprinos: 19 g, (98%) . M.p. 107°C. Sodium cyanoborohydride (24 g, 400 mmol) was added gradually over half an hour to a suspension of 5,10-dihydroindeno[1,2-b]indole (19.16 g, 93 mmol) in glacial acetic acid (300 cm3). The mixture was stirred for 3 hours, until all the material was dissolved. The solution was poured into ice water (500 cm3) and stirred for 1 hour to dissolve the borohydride complex. The clear solution was then carefully neutralized with sodium hydroxide, which caused a white precipitate to form. The precipitate was filtered and washed with water until the washings were free of cyanide ions. Drying gave the title compound as a white solid. Contribution: 19 g, (98%) . MP 107°C.

1H NMR (CDCl3) δ:3.20 (1H, dd,), 3.51 (1H, dd), 3.99 1H, br,) 4.18 (1H, ddd,), 5.25 (1H, d) 6.60 (1H, d,), 6.74 (1H, dd,), 6.99 (1H, dd), 7.15-7.22 (4H, m,), 7.32 (1H, d,), 1H NMR (CDCl3) δ: 3.20 (1H, dd,), 3.51 (1H, dd), 3.99 1H, br,) 4.18 (1H, ddd,), 5.25 (1H, d) 6.60 (1H, d,), 6.74 (1H, dd), 6.99 (1H, dd), 7.15-7.22 (4H, m), 7.32 (1H, d),

Primjer 2 Example 2

cis-4b,5,9b,10-Tetrahidro-5-metilindeno[1,2-b]indol cis-4b,5,9b,10-Tetrahydro-5-methylindeno[1,2-b]indole

Balon sušen na vatri napunjen je natrijevim hidridom (60 mg, 2.5 mmol) i tetrahidrofuranom (THF) (5 cm3), pod atmosferom dušika. U miješanu suspenziju je dodan cis-4b,5,9b,10-tetrahidroindeno[1,2-b]indol (500 mg, 2.4 mmol) u THF (5 cm3), u kapima. Smjesa je miješana 1 sat, za koje vrijeme se razvila roza boja. Dodan je jodometan (0.2 cm3), pa je otopina miješana preko noći. Dodana je voda (5 cm3), pa je THF stavljen pod vakuum. Tako dobivena bezbojna kruta supstancija je filtrirana i sušena u vakuumskom eksikatoru. Proizvod je otopljen u 5% etil acetat/petrol eteru (60-80°C i filtriran je kroz jastučić od silikagela sa fleš-kromatografijom. Nakon isparavanja otapala pod vakuumom, naslovni spoj je dobiven kao bezbojna kruta supstancija. A flame-dried flask was filled with sodium hydride (60 mg, 2.5 mmol) and tetrahydrofuran (THF) (5 cm3), under a nitrogen atmosphere. To the stirred suspension was added cis-4b,5,9b,10-tetrahydroindeno[1,2-b]indole (500 mg, 2.4 mmol) in THF (5 cm3), dropwise. The mixture was stirred for 1 hour, during which time a pink color developed. Iodomethane (0.2 cm3) was added, and the solution was stirred overnight. Water (5 cm3) was added, and the THF was placed under vacuum. The colorless solid thus obtained was filtered and dried in a vacuum desiccator. The product was dissolved in 5% ethyl acetate/petroleum ether (60-80°C) and filtered through a silica gel pad with flash chromatography. After evaporation of the solvent under vacuum, the title compound was obtained as a colorless solid.

Doprinos: 450 mg (85%). T.t. 76-77°C Contribution: 450 mg (85%). T.t. 76-77°C

1H NMR (CDCl3) δ : 3.0 (3H, s,), 3.1 (1H, dd,), 3.4 (1H, dd,), 4.1 (1H, ddd,), 4.9 (1H, d,), 6.4 (1H, d,), 6.7 (1H, dd,) 7.1-7.5 (6H, m,). 1H NMR (CDCl3) δ : 3.0 (3H, s,), 3.1 (1H, dd,), 3.4 (1H, dd,), 4.1 (1H, ddd,), 4.9 (1H, d,), 6.4 (1H , d,), 6.7 (1H, dd,) 7.1-7.5 (6H, m,).

Primjer 3 Example 3

5,10-Dihidro-8metoksiindeno[1,2-b]indol (770 mg, 3.3 mmol) je reagirao s natrijevim cijanoborohidridom (1.0 g, 16 mmol) u glacijalnoj octenoj kiselini (17 cm3). Nakon 30 minuta smjesa je prosuta u smjesu led/voda, miješana 1 sat i neutralizirana s natrijevim hidroksidom. Bezbojna reakcijska smjesa je ekstrahirana s detil eterom, organski spoj je odvojen, sušen (Na2SO4) i koncentriran pod vakuumom. Ostatak je kromatografiran na koloni (10% etil acetat/petrol eter 60-80°C, pa je dao naslovni spoj kao bezbojnu krutu supstanciju. Doprinos: 520 mg (66%). T.t. 5,10-Dihydro-8methoxyindeno[1,2-b]indole (770 mg, 3.3 mmol) was reacted with sodium cyanoborohydride (1.0 g, 16 mmol) in glacial acetic acid (17 cm3). After 30 minutes, the mixture was poured into an ice/water mixture, stirred for 1 hour and neutralized with sodium hydroxide. The colorless reaction mixture was extracted with diethyl ether, the organic compound was separated, dried (Na2SO4) and concentrated under vacuum. The residue was column chromatographed (10% ethyl acetate/petroleum ether 60-80°C) to give the title compound as a colorless solid. Yield: 520 mg (66%). T.p.

101°C. H1 NMR (CDCl3) δ : 3.28 (1H, dd,), 3.57 (1H, dd,), 3.80 (3H, s,), 3.85 (1H, br,), 4.24 (1H, dd,), 5.30 (1H, d,), 6.6-7.4 (7H, m). 101°C. H1 NMR (CDCl3) δ : 3.28 (1H, dd,), 3.57 (1H, dd,), 3.80 (3H, s,), 3.85 (1H, br,), 4.24 (1H, dd,), 5.30 (1H , d, ), 6.6-7.4 (7H, m).

Primjer 4 Example 4

Korištenjem istog postupka koji je opisan u Primjeru 2, cis-4b,5,9b,10-tetrahidro-8-metoksiindeno[1,2-b]indol (239 mg, 1.0 mmol) je metiliran s jodometanom uz korištenje natrijevog hidrida (25 mg, 1.1 mmol) kao baze u THF (2 cm3). Ekstrakcija da dietileterom i pričvršćivanjem vakuumskom fleš-kromatografijom dali su prozirnu gumu. Doprinos: 158 mg (63%) koji su očvrsnuli nakon destilacije iz balona u balon (180°C na 0.2 mm Hg), čime je dobiven naslovni spoj, t.t. 72°C. Using the same procedure as described in Example 2, cis-4b,5,9b,10-tetrahydro-8-methoxyindeno[1,2-b]indole (239 mg, 1.0 mmol) was methylated with iodomethane using sodium hydride (25 mg, 1.1 mmol) as base in THF (2 cm3). Extraction with diethyl ether and fixation by vacuum flash chromatography gave a clear gum. Yield: 158 mg (63%) which solidified after distillation from flask to flask (180°C at 0.2 mm Hg) to give the title compound, m.p. 72°C.

1H NMR (CDCl3) δ : 2.87 (3H, s,), 3.03 (1H, dd,), 3.36 (1H,dd), 3.70 (3H, s,), 4.08 (1H, ddd,), 4.80 (1H, d,), 6.28 (1H, d,), 6.61 (1H, dd,), 6.77 (1H, dd,), 7.1-7.5 (4H, m,). 1H NMR (CDCl3) δ : 2.87 (3H, s,), 3.03 (1H, dd,), 3.36 (1H, dd), 3.70 (3H, s,), 4.08 (1H, ddd,), 4.80 (1H, d,), 6.28 (1H, d,), 6.61 (1H, dd,), 6.77 (1H, dd,), 7.1-7.5 (4H, m,).

Primjer 5 Example 5

cis-5,5a,6,10b-Tetrahidroindeno[2,1-b]indol cis-5,5a,6,10b-Tetrahydroindeno[2,1-b]indole

5,6-Dihidroindeno[2,1-b]indol (185 mg, 0.9 mmol) je reagirao sa natrijevim cijanoborohidridom (310 mg, 5 mmol) u glacijalnoj octenoj kiselini (5 cm3) tokom 6 sati. Otopina je prosuta u led/vodu i miješana jedan sat. zatim je neutralizirana s natrijevim hidroksidom, pa je dobivena bijela kruta supstancija prikupljena filtriranjem, isprana vodom, sušena i prečišćena fleš-kromatografijom (10% EtOAc/petrol eter 60-80°C), Rf 30% EtOAc/petrol eter (60-80°C) = 0.6), da bi se dobio naslovni spoj kao bezbojna kruta supstancija. Doprinos: (81 mg, (43%) M.p. 85-86°C. 5,6-Dihydroindeno[2,1-b]indole (185 mg, 0.9 mmol) was reacted with sodium cyanoborohydride (310 mg, 5 mmol) in glacial acetic acid (5 cm3) for 6 h. The solution was poured into ice/water and stirred for one hour. then it was neutralized with sodium hydroxide, and the resulting white solid was collected by filtration, washed with water, dried and purified by flash chromatography (10% EtOAc/petroleum ether 60-80°C), Rf 30% EtOAc/petroleum ether (60-80 °C) = 0.6), to obtain the title compound as a colorless solid. Contribution: (81 mg, (43%) M.p. 85-86°C.

1H (CDCl3) δ : 3.09 (1H, dd,), 3.33 (1H, dd,), 3.45 (1H, br,), 4.74 (1H, d,), 4.82 (1H, ddd,), 6.55 (1H, ddd,), 6.73 (1H, ddd,), 7.00 (1H, ddd,), 7.1-7.4 (4H, m). 1H (CDCl3) δ : 3.09 (1H, dd,), 3.33 (1H, dd,), 3.45 (1H, br,), 4.74 (1H, d,), 4.82 (1H, ddd,), 6.55 (1H, ddd, ), 6.73 (1H, ddd, ), 7.00 (1H, ddd, ), 7.1-7.4 (4H, m).

Primjer 6 Example 6

cis-4b,5,9b,10-Tetrahidro-10,10-dimetiliindeno[1,2-b]indol cis-4b,5,9b,10-Tetrahydro-10,10-dimethylindeno[1,2-b]indole

5,10-Dihidro-10,10-dimetilindeno[1,2-b]indol (1.00 g, 4.29 mmol) je reagirao s natrijevim cijanoborohidridom (1.0 g, 16 mmol) u glacijalnoj octenoj kiselini (20 cm3) tokom 10 minuta. Otopina je prosuta u vodu, miješana 30 minuta, i ekstrahirana sa dietil eterom. Organska faza je ispirana 10 puta s vodom, sušena (Na2SO4) i otapalo je stavljeno pod vakuum. Ostatak je otopljen u 5% etilacetat/petrol eteru (60-80°C) i filtriran kroz jastuke od silikagela za fleš-kromatografiju da bi se, nakon uklanjanja otapala, dobila guma koja je očvrsnula na uljnoj pumpi da bi dala naslovni spoj kao bezbojnu krutu supstanciju. Doprinos: 0.98 g (98%), t.t. 57-59°C 5,10-Dihydro-10,10-dimethylindeno[1,2-b]indole (1.00 g, 4.29 mmol) was reacted with sodium cyanoborohydride (1.0 g, 16 mmol) in glacial acetic acid (20 cm3) for 10 min. The solution was poured into water, stirred for 30 minutes, and extracted with diethyl ether. The organic phase was washed 10 times with water, dried (Na 2 SO 4 ) and the solvent was placed under vacuum. The residue was dissolved in 5% ethyl acetate/petroleum ether (60-80°C) and filtered through silica gel pads for flash chromatography to give, after removal of the solvent, a gum which solidified on an oil pump to give the title compound as a colorless solid substance. Contribution: 0.98 g (98%), m.t. 57-59°C

1H NMR (CDCl3) δ : 1.17 (3H, s,), 1.43 (3H, s,), 3.86 (1H, d,), 3.9 (1H, br,), 5.29 (1H, d,), 6.59 (1H, d,), 6.71 (1H, ddd,), 7.02 (1H, ddd,), 7.2-7.3 (5H, m,). 1H NMR (CDCl3) δ : 1.17 (3H, s,), 1.43 (3H, s,), 3.86 (1H, d,), 3.9 (1H, br,), 5.29 (1H, d,), 6.59 (1H , d, ), 6.71 (1H, ddd, ), 7.02 (1H, ddd, ), 7.2-7.3 (5H, m, ).

Primjer 7 Example 7

Fenilhidrazon 2-metil -1-indanona (1.44 g, 6.1 mmol) je zagrijan u dietilen glikolu (20 cm3) do blizu temperature refluksa, sve dok se iz zračnog kondenzatora nije počeo razvijati amonijak. Zagrijavanje je nastavljeno preko noći ili do prestanka izdvajanja amonijaka. Otopina je ohlađena, prosuta u podjednaku zapremninu vode i ekstrahirana sa detil eterom. Eterska otopina je ponovno ekstrahirana sa 2M klorovodikovom kiselinom, koja je alkalizirana s natrijevim hidroksidom, pa je izvršena još jedna ekstrakcija sa detil eterom. Ekstrakti su ispareni i ostatak je prečišćen kromatografijom na koloni silikagela uz eluiranje sa 5% EtOAc/petrol eterom, da bi se dobio naslovni spoj kao bezbojna kruta supstancija (Rf 30% EtOAc/petrol eter = 0.8). Doprinos: 28% T.t. 72°C. Phenylhydrazone 2-methyl-1-indanone (1.44 g, 6.1 mmol) was heated in diethylene glycol (20 cm3) to near reflux temperature, until ammonia began to evolve from the air condenser. Heating was continued overnight or until ammonia evolution ceased. The solution was cooled, poured into an equal volume of water and extracted with diethyl ether. The ethereal solution was re-extracted with 2M hydrochloric acid, which was made alkaline with sodium hydroxide, and another extraction with diethyl ether was performed. The extracts were evaporated and the residue was purified by silica gel column chromatography eluting with 5% EtOAc/petroleum ether to give the title compound as a colorless solid (Rf 30% EtOAc/petroleum ether = 0.8). Contribution: 28% T.t. 72°C.

1H NMR (CDCl3) δ : 1.46 (3H, s,), 1.43 (3H, s,), 3.86 (1H, d,), 3.9 (1H, br,), 5.29 (1H, d,), 6.59 (1H, d,), 6.71 (1H, ddd,), 7.02 (1H, ddd,), 7.2-7.3 (5H, m,). 1H NMR (CDCl3) δ : 1.46 (3H, s,), 1.43 (3H, s,), 3.86 (1H, d,), 3.9 (1H, br,), 5.29 (1H, d,), 6.59 (1H , d, ), 6.71 (1H, ddd, ), 7.02 (1H, ddd, ), 7.2-7.3 (5H, m, ).

Primjer 7 Example 7

cis-4b,5-9b-10-Tetrahidro-9b-metilindeno[1,2-b]indol cis-4b,5-9b-10-Tetrahydro-9b-methylindeno[1,2-b]indole

Fenilhidrazon 2-metil-1-indanona (1.44 g, 6.1 mmol) je zagrijan u dietilen glikolu (29 cm3) do blizu temperature refluksa, sve dok se iz zračnog kondenzatora nije počeo razvijati amonijak. Zagrijavanje je nastavljeno preko noći ili do prestanka izdvajanja amonijaka. Otopina je ohlađena, prosuta u podjednaku zapremninu vode i ekstrahirana sa detil eterom. Eterska otopina je ponovno ekstrahirana sa 2M klorovodikovom kiselinom, koja je alkalizirana s natrijevim hidroksidom, pa je izvršena još jedna ekstrakcija sa detil eterom. Ekstrakti su ispirani i ostatak je prečišćen kromatografijom na koloni silikalega uz eluiranje sa 5% EtOAc/petrol eterom, da bi se dobio naslovni spoj kao bezbojna kruta supstancija (Rf 30% EtOAc/petrol eter = 0.8). Doprinos: 28% T.t. 72°C. Phenylhydrazone 2-methyl-1-indanone (1.44 g, 6.1 mmol) was heated in diethylene glycol (29 cm3) to near reflux until ammonia began to evolve from the air condenser. Heating was continued overnight or until ammonia evolution ceased. The solution was cooled, poured into an equal volume of water and extracted with diethyl ether. The ethereal solution was re-extracted with 2M hydrochloric acid, which was made alkaline with sodium hydroxide, and another extraction with diethyl ether was performed. The extracts were washed and the residue was purified by silica gel column chromatography eluting with 5% EtOAc/petroleum ether to give the title compound as a colorless solid (Rf 30% EtOAc/petroleum ether = 0.8). Contribution: 28% T.t. 72°C.

1H NMR (CDCl3) δ : 1.46 (3H, s,), 3.10 (1H, d,), 3.30 (1H, dd,), 4.05 (1H, s,), 4.69 (1H, s,), 6.52 (1H, dd,), 6.71 (1H, ddd,), 6.95 (1H, ddd,), 7.0-7.2 (5H, m,). 1H NMR (CDCl3) δ : 1.46 (3H, s,), 3.10 (1H, d,), 3.30 (1H, dd,), 4.05 (1H, s,), 4.69 (1H, s,), 6.52 (1H , dd, ), 6.71 (1H, ddd, ), 6.95 (1H, ddd, ), 7.0-7.2 (5H, m, ).

Primjer 8 Example 8

cis-4b,5-9b-10-Tetrahidro-4b,9b-dimetilindeno[1,2-b]indol cis-4b,5-9b-10-Tetrahydro-4b,9b-dimethylindeno[1,2-b]indole

Metillitij (1.5 ml, 2 ekvivalenta 1.5 M otopine u heksanu) je u kapima, na - 78°C, dodana otopini 9b,10-dihidro-9b-metilindeno[1,2-b]indola (260 mg, 1.19 mmol) u THF (10cm3). Nakon miješanja na -78°C tokom 1 sat, tamno crvenoj otopini je dodana voda (1 cm3) pa je reakcijska smjesa ostavljena da se zagrije. Blizu sobne temperature, nestala je boja otopine. Reakcija je prekinuta dodatkom zasićene otopine amonij klorida (10 cm3), organska faza je odvojena, i sušena (Na2SO4). Isparavanje otapala si fleš-kromatografija (10% EtOAc/petrol eter [60-80°C]) dali su bezbojnu gumu (Rf [10% EtOAc/petrol eter (60-80°C)] = 0.5 koja je očvrsnula nakon što je cjelokupno zaostalo otapalo uklonjeno pomoću uljne pumpe. Time je dobiven naslovni spoj kao bezbojna kruta supstancija. Doprinos: 87 mg (31%). Methyllithium (1.5 ml, 2 equivalents of a 1.5 M solution in hexane) was added dropwise at -78°C to a solution of 9b,10-dihydro-9b-methylindeno[1,2-b]indole (260 mg, 1.19 mmol) in THF (10 cm 3 ). After stirring at -78°C for 1 hour, water (1 cm3) was added to the dark red solution and the reaction mixture was allowed to warm up. Close to room temperature, the color of the solution disappeared. The reaction was terminated by the addition of saturated ammonium chloride solution (10 cm3), the organic phase was separated and dried (Na2SO4). Solvent evaporation and flash chromatography (10% EtOAc/petroleum ether [60-80°C]) gave a colorless gum (Rf [10% EtOAc/petroleum ether (60-80°C)] = 0.5) which solidified after all residual solvent was removed using an oil pump to give the title compound as a colorless solid.Yield: 87 mg (31%).

1H NMR (CDCl3) δ : 1.35 (3H, s,), 1.46 (3H, s,), 3,07 (1H, d,), 3.36 (1H, d,), 4,27 (1H, br,), 6.53 (1H,), 6.71 (1H, ddd,), 6,96 (1H, ddd,), 7.1-7.3 (5H, m,). 1H NMR (CDCl3) δ : 1.35 (3H, s,), 1.46 (3H, s,), 3.07 (1H, d,), 3.36 (1H, d,), 4.27 (1H, br,) , 6.53 (1H, ), 6.71 (1H, ddd, ), 6.96 (1H, ddd, ), 7.1-7.3 (5H, m, ).

Primjer 9 Example 9

cis-4b,5-9b-10-Tetrahidro-6,8-dimetilindeno[1,2-b]indol cis-4b,5-9b-10-Tetrahydro-6,8-dimethylindeno[1,2-b]indole

5,10-Dihidro-6,8-dimetilindeno[1,2-b]indol (323 mg, 1.38 mmol) je reagirao sa natrijevim cijanoborohidridom (400 mg, 5 ekvivalenata) u glacijalnoj octenoj kiselini (7 cm3) tokom 30 minuta. Otopina je prosuta u led/vodu i miješana je još 30 minuta. 5,10-Dihydro-6,8-dimethylindeno[1,2-b]indole (323 mg, 1.38 mmol) was reacted with sodium cyanoborohydride (400 mg, 5 equivalents) in glacial acetic acid (7 cm3) for 30 minutes. The solution was poured into ice/water and stirred for another 30 minutes.

Vodena otopina je neutralizirana natrijevim hidroksidom, pa je suspenzija ekstrahirana sa dietil eterom. Organski ekstrakti su isprani vodom, sušeni (Na2SO4) i ispareni pod vakuumom. Prečišćavanje vakuumskom fleš-kromatografijom dalo je naslovni spoj kao bezbojnu krutu supstanciju. Doprinos: 2.44 mg. (75%) . M.p. 147°C The aqueous solution was neutralized with sodium hydroxide, and the suspension was extracted with diethyl ether. The organic extracts were washed with water, dried (Na2SO4) and evaporated under vacuum. Purification by vacuum flash chromatography afforded the title compound as a colorless solid. Contribution: 2.44 mg. (75%) . MP 147°C

(from EtOAc/petrol [60-80°C]). 1H NMR (CDCl3) δ : 2.03 and 2.07 (3H, s,), 3.18 (1H, dd,), 3,48 (1H, dd,), 4.16 (1H, ddd,), 5.24 (1H, d,), 6.66 (1H, s,), 6.84 (1H, s,), 7.1-7.4 (4H, m,). (from EtOAc/petrol [60-80°C]). 1H NMR (CDCl3) δ : 2.03 and 2.07 (3H, s,), 3.18 (1H, dd,), 3.48 (1H, dd,), 4.16 (1H, ddd,), 5.24 (1H, d,) , 6.66 (1H, s, ), 6.84 (1H, s, ), 7.1-7.4 (4H, m, ).

Primjer 10 Example 10

cis-4b,5-9b-10-Tetrahidro-8-metilindeno[1,2-b]indol cis-4b,5-9b-10-Tetrahydro-8-methylindeno[1,2-b]indole

5,10-Dihidro-8-metilindino[1,2-b]indol (10 g, 46 mmol) je miješan na sobnoj temperaturi u gracijalnoj octenoj kiselini (150 cm3). U partijama je, tokom 30 minuta, dodat natrijev cijanoborohidrid (8.6 g. 3 ekvivalenta) Reakcijska smjesa je miješana još 1 sat i zatim je prosuta u led/vodu (200 cm3). Nakon 30 minuta miješanja, kisela otopina je alkalizirana dodatkom natrijevog hidroksida, pa je formirana bezbojna kruta supstancija prikupljena filtriranjem. Ova kruta supstancija je pažljivo ispirana, sve dok ostatak nije bio oslobođen od cijanidnih iona, a zatim je sušena pod vakuumom da bi dala naslovni spoj kao bezbojnu krutu supstanciju. Doprinos: 7.5 g. (73%) . T.t. 110°C 5,10-Dihydro-8-methylindino[1,2-b]indole (10 g, 46 mmol) was stirred at room temperature in acetic acid (150 cm 3 ). Sodium cyanoborohydride (8.6 g. 3 equivalents) was added in batches over 30 minutes. The reaction mixture was stirred for another 1 hour and then poured into ice/water (200 cm3). After stirring for 30 minutes, the acidic solution was alkalized by the addition of sodium hydroxide, and a colorless solid was formed and collected by filtration. This solid was carefully washed until the residue was free of cyanide ions and then dried under vacuum to give the title compound as a colorless solid. Contribution: 7.5 years (73%) . T.t. 110°C

(from ethanol/water). 1H NMR (CDCl3) δ : 2.24 (3H, s,), 3.20 (1H, dd,), 3,50 (1H, dd,), 3.9 (1H, br,), 4.16 (1H, dd,), 5.23 (1H, d,), 6.25 (1H, d,), 6.80 (1H, s), 7.1-7.4 (4H, m,). (from ethanol/water). 1H NMR (CDCl3) δ : 2.24 (3H, s,), 3.20 (1H, dd,), 3.50 (1H, dd,), 3.9 (1H, br,), 4.16 (1H, dd,), 5.23 (1H, d, ), 6.25 (1H, d, ), 6.80 (1H, s), 7.1-7.4 (4H, m, ).

Primjer 11 Example 11

cis-4b,5-9b-10-Tetrahidro-5,8-dimetilindeno[1,2-b]indol cis-4b,5-9b-10-Tetrahydro-5,8-dimethylindeno[1,2-b]indole

Rastvor cis-4b,5,9b,10-tetrahidro-8-metilindeno[1,2-b]indola (1.8 g, 8.1 mmol) u THF (20 cm3) je ohlađen do -78°C i u kapima je dodan n-butillitij (5.6 cm 1.6 M otopine u heksanu, 9.0 mmol). Temperatura otopine je ostavljena da se zagrije do sobne pa je miješanje vršeno tokom 30 minuta. Smjesa je zatim ohlađena do -78°C i dodan je jodometan (0.6 cm3, 0.9 mmol). Reakcijska smjesa je ponovno ostavljena da se polako zagrije do sobne temperature i reakcija je prekinuta dodatkom zasićene otopine aminijevog klorida (5 cm3). Nakon miješanja preko noći, organski sloj je razblažen sa diklorometanom, odvojen, ispran slanom otopinom i sušen (MgSO4). Nakon uklanjanja otapala pod vakuumom, ostatak je prečišćen kromatografijom na koloni da bi dao gumu, koja je nakon trituriranja s etanolom dala naslovni spoj kao bezbojnu krutu supstanciju. Doprinos: 1.0 g. (53%) . T.t. 54°C A solution of cis-4b,5,9b,10-tetrahydro-8-methylindeno[1,2-b]indole (1.8 g, 8.1 mmol) in THF (20 cm3) was cooled to -78°C and n- butyllithium (5.6 cm of a 1.6 M solution in hexane, 9.0 mmol). The temperature of the solution was allowed to warm up to room temperature, so mixing was carried out for 30 minutes. The mixture was then cooled to -78°C and iodomethane (0.6 cm3, 0.9 mmol) was added. The reaction mixture was again allowed to slowly warm to room temperature and the reaction was quenched by the addition of a saturated solution of amine chloride (5 cm 3 ). After stirring overnight, the organic layer was diluted with dichloromethane, separated, washed with brine and dried (MgSO4). After removal of the solvent under vacuum, the residue was purified by column chromatography to give the gum, which after trituration with ethanol gave the title compound as a colorless solid. Contribution: 1.0 g. (53%) . T.t. 54°C

(from ethanol). 1H NMR (CDCl3) δ : 2.25 (3H, s,), 2.94 (3H, s,), 3,07 (1H, dd,), 3.41 (1H, dd,), 4.11 (1H, m,), 4.88 (1H, d,), 6.30 (1H, d,), 6.88 (1H, d,), 3.96 (1H, d,), 7.1-7.4 (4H, m,). (from ethanol). 1H NMR (CDCl3) δ : 2.25 (3H, s,), 2.94 (3H, s,), 3.07 (1H, dd,), 3.41 (1H, dd,), 4.11 (1H, m,), 4.88 (1H, d, ), 6.30 (1H, d, ), 6.88 (1H, d, ), 3.96 (1H, d, ), 7.1-7.4 (4H, m, ).

Primjer 12 Example 12

cis-4b,5-9b-10-Tetrahidro-8-izo-propilindeno[1,2-b]indol cis-4b,5-9b-10-Tetrahydro-8-iso-propylindeno[1,2-b]indole

5,10-Dihidro-8-izo-propilindeno[1,2-b]indol (5.27 g, 21.3 mmol) je miješan na sobnoj temperaturi u glacijalnoj octenoj kiselini (100 cm3). Postupno je, tokom 30 minuta, dodat natrijev cijanoborohidrid (5 g, 3 ekvivalenta). Smjesa je miješana 30 min. i zatim je prosuta u led/vodu (150 cm3). Nakon 30 minuta miješanja, otopina je neutralizirana s vodenom otopinom natrijevog hidroksida pa je tako dobivena bezbojna kruta supstancija prikupljena filtriranjem. Kruta supstancija je isprana više puta s vodom, sve dok ostatak nije oslobođen od cijanidnih iona, pa je sušen pod vakuumom da bi dao naslovni spoj kao bezbojnu krutu supstanciju. Doprinos: 3.5 g. (61%) . M.p. 104°C [from petrol (60-80°C)]. 1H NMR (CDCl3) δ : 1.19 (6H, s,), 2.80 (1H, septet,), 3,20 (1H, dd,), 3.48 (1H, dd,), 4.07 (1H, ddd,), 5.21 (1H, d,), 6.53 (1H, d,), 6.86 (1H, dd,), 7.03 (1H, s,), 7.1-7.4 (4H, m,). 5,10-Dihydro-8-iso-propylindeno[1,2-b]indole (5.27 g, 21.3 mmol) was stirred at room temperature in glacial acetic acid (100 cm3). Sodium cyanoborohydride (5 g, 3 equivalents) was added gradually over 30 minutes. The mixture was stirred for 30 min. and then poured into ice/water (150 cm3). After 30 minutes of mixing, the solution was neutralized with an aqueous solution of sodium hydroxide, thus obtaining a colorless solid substance collected by filtration. The solid was washed several times with water until the residue was free of cyanide ions, then dried under vacuum to give the title compound as a colorless solid. Contribution: 3.5 years (61%) . MP 104°C [from petrol (60-80°C)]. 1H NMR (CDCl3) δ : 1.19 (6H, s,), 2.80 (1H, septet,), 3.20 (1H, dd,), 3.48 (1H, dd,), 4.07 (1H, ddd,), 5.21 (1H, d, ), 6.53 (1H, d, ), 6.86 (1H, dd, ), 7.03 (1H, s, ), 7.1-7.4 (4H, m, ).

Primjer 13 Example 13

cis-4b,5-9b-10-Tetrahidro-5-metil-8-izo-propilindeno[1,2-b]indol cis-4b,5-9b-10-Tetrahydro-5-methyl-8-iso-propylindeno[1,2-b]indole

Otopina cis-4b,5-9b-10-tetrahidro-8-izo-propilindeno[1,2-b]indola (1.75 g, 7.0 mmol) u THF (10 cm3) dodana je suspenzija natrijevog hidrida (200 mg, 1.2 ekvivalenta) u THF (7 cm3) na 0°C. Smjesa je miješana preko noći i reakcija je zatim prekinuta dodatkom zasićene otopine amonijevog klorida. Organske faze su odvojene, pa je vodena faza ekstrahirana sa dietil eterom. Kombinirane organske faze su sušene (NaSO4), pa je otapalo stavljeno pod vakuum da bi dalo naslovni spoj kao bezbojnu gumu koja je pričvršćena destilacijom iz balona u balon. Doprinos: 1.0 g T.klj. 200°C (0.4 mm) To a solution of cis-4b,5-9b-10-tetrahydro-8-iso-propylindeno[1,2-b]indole (1.75 g, 7.0 mmol) in THF (10 cm3) was added a suspension of sodium hydride (200 mg, 1.2 equiv. ) in THF (7 cm3) at 0°C. The mixture was stirred overnight and the reaction was then quenched by the addition of saturated ammonium chloride solution. The organic phases were separated, and the aqueous phase was extracted with diethyl ether. The combined organic phases were dried (NaSO 4 ) and the solvent was removed under vacuum to give the title compound as a colorless gum which was solidified by flask-to-flask distillation. Contribution: 1.0 g T.klj. 200°C (0.4 mm)

1H NMR (CDCl3) δ : 1.22 (6H, d,), 2.81 (1H, septet,), 2,94 (3H, s,), 3.09 (1H, dd,), 3.43 (1H, dd,), 4.15 (1H, ddd,), 4.90 (1H, d,), 6.32 (1H, d,), 6.93 (1H, dd,), 7.02 (1H, br,), 7.1-7.4 (4H, m,). 1H NMR (CDCl3) δ : 1.22 (6H, d,), 2.81 (1H, septet,), 2.94 (3H, s,), 3.09 (1H, dd,), 3.43 (1H, dd,), 4.15 (1H, ddd, ), 4.90 (1H, d, ), 6.32 (1H, d, ), 6.93 (1H, dd, ), 7.02 (1H, br, ), 7.1-7.4 (4H, m, ).

Primjer 14 Example 14

cis-4b,5-9b-10-Tetrahidro-2-metoksi-1,3-dimetilindeno[1,2-b]indol cis-4b,5-9b-10-Tetrahydro-2-methoxy-1,3-dimethylindeno[1,2-b]indole

5,10-Dihidro-2-metoksi-1,3-dimetilindeno[1,2-b]indol (1 g, 3.80 mmol) je miješan na sobnoj temperaturi u glacijalnoj octenoj kiselini (15 cm3). Dodana je natrijev borohidrid (0.75 g, 3 ekvivalanta) postupno, tokom 15 minuta, pa je smjesa miješana još 2 sata. Smjesa je prosuta u led/vodu (30 cm3), te je miješanje nastavljeno još 30 minuta. Otopina je neutralizirana s vodenom otopinom natrijevog hidroksida i ekstrahirana sa dietil eterom. Organski ekstrakti su pažljivo ispirani vodom sve dok ostatak nije oslobođen od cijanidnih iona. Otapalo je stavljeno pod vakuum da bi se dibio naslovni spoj. Ovaj spoj je prečišćen kromatografijom na koloni, da bi dao bezbojnu krutu supstanciju. Doprinos: 0.8 g /79%). T.t. 117°C iz EtOAc/petrol etera (60-80°C). Elementarna analiza: Nađeno: C 81.6, H 7.3, N 5.8, izračunato za C18H19NO: C 81.5 H 7.2, N 5,10-Dihydro-2-methoxy-1,3-dimethylindeno[1,2-b]indole (1 g, 3.80 mmol) was stirred at room temperature in glacial acetic acid (15 cm3). Sodium borohydride (0.75 g, 3 equivalents) was added gradually over 15 minutes, and the mixture was stirred for another 2 hours. The mixture was poured into ice/water (30 cm3), and mixing was continued for another 30 minutes. The solution was neutralized with aqueous sodium hydroxide solution and extracted with diethyl ether. The organic extracts were carefully washed with water until the residue was freed from cyanide ions. The solvent was placed under vacuum to remove the title compound. This compound was purified by column chromatography to give a colorless solid. Contribution: 0.8 g /79%). T.t. 117°C from EtOAc/petroleum ether (60-80°C). Elemental analysis: Found: C 81.6, H 7.3, N 5.8, calculated for C18H19NO: C 81.5 H 7.2, N

5.9 1H NMR (CDCl3) : δ : 2.15 (3H, s,), 2.25 (3H, s,), 3,07 (1H, dd,), 3.36 (1H, dd,), 3.64 (3H, s,), 4.1 (1H, br,), 4.19 (1H, ddd,), 5.20 (1H, d,), 6.60 (1H, d,), 6.74 (1H, ddd,), 6.97 (1H, s,), 7.00 (1H, ddd,), 7.17 (1H, d,). 5.9 1H NMR (CDCl3) : δ : 2.15 (3H, s,), 2.25 (3H, s,), 3.07 (1H, dd,), 3.36 (1H, dd,), 3.64 (3H, s,) , 4.1 (1H, br,), 4.19 (1H, ddd,), 5.20 (1H, d,), 6.60 (1H, d,), 6.74 (1H, ddd,), 6.97 (1H, s,), 7.00 (1H, ddd, ), 7.17 (1H, d, ).

Primjer 15 Example 15

cis-4b,5-9b-10-Tetrahidro-4b,6,8,9b-tetrametilindeno[1,2-b]indol cis-4b,5-9b-10-Tetrahydro-4b,6,8,9b-tetramethylindeno[1,2-b]indole

Smjesa 5.1 g (0.03 mol) 2,4-dimetilfenilhidrazin klorohidrata, 5.4 g (0.003 mol) 2-metil-1-indanona, 100 ml etanola (99.5%) i 2.5 ml konc. klorovodikove kiseline refluksirana je tokom 2 sata. Dobivena smjesa je filtrirana, filtrat je isparen a ostatak je podijeljen između etera i vode. Organska baza je isprana s vodenom otopinom natrijevog karbonata, sušena (MgSO4), filtrirana i isparena. Ostatak je podvrgnut fleš-kromatografiji na silikagelu od 60°C. Nakon eluiranja nepolarnih nečistoća sa diklormetan/izooktanom (1/1), smjesa metanol/etil acetat/heksana (1/4/5) je eluirala 5 g sirovog 9b,10-dihidro-6,8,9b-trimetilindeno[1,2-b]indola. Ovaj materijal je, bez daljnjeg prečišćavanja, otopljen u 100 ml suhog THF. Pod atmosferom argona, na -65 do -55°C, dodano je 50 ml 1.6 metil litija u eteru. Dobivena smjesa je držana na -78°C tokom 1 sat i zatim je prosuta u hladnu vodenu otopinu amonijevog klorida. Smjesa je ekstrahirana sa eterom i kombinirani organski slojevi su isparavani da bi dali 5 g zelenog ulja. Kromatografija na silikagelu od 60°C, uz korištenje 7.5% etil acetata u izooktanu, dala je 1 g naslovnog spoja. A mixture of 5.1 g (0.03 mol) of 2,4-dimethylphenylhydrazine chlorohydrate, 5.4 g (0.003 mol) of 2-methyl-1-indanone, 100 ml of ethanol (99.5%) and 2.5 ml of conc. of hydrochloric acid was refluxed for 2 hours. The resulting mixture was filtered, the filtrate was evaporated and the residue was partitioned between ether and water. The organic base was washed with aqueous sodium carbonate solution, dried (MgSO4), filtered and evaporated. The residue was subjected to flash chromatography on silica gel at 60°C. After elution of non-polar impurities with dichloromethane/isooctane (1/1), a mixture of methanol/ethyl acetate/hexane (1/4/5) eluted 5 g of crude 9b,10-dihydro-6,8,9b-trimethylindeno[1,2 -b]indole. This material, without further purification, was dissolved in 100 ml of dry THF. Under an atmosphere of argon, at -65 to -55°C, 50 ml of 1.6 methyl lithium in ether was added. The resulting mixture was kept at -78°C for 1 hour and then poured into a cold aqueous solution of ammonium chloride. The mixture was extracted with ether and the combined organic layers were evaporated to give 5 g of a green oil. Chromatography on silica gel at 60°C, using 7.5% ethyl acetate in isooctane, gave 1 g of the title compound.

1H NMR (CDCl3); 1,37 (3H, s,), 1.48 (3H, s,), 2,07 (3H, s,), 2.20 (3H, s,), 3.00-3.35 (2H, AB-system, J 15 Hz), 3.9 (1H, bs,), 6.60 (1H, s,), 6.88 (1H, s,), 7.08-7.28 (4H, m). 1H NMR (CDCl3); 1.37 (3H, s,), 1.48 (3H, s,), 2.07 (3H, s,), 2.20 (3H, s,), 3.00-3.35 (2H, AB-system, J 15 Hz) , 3.9 (1H, bs, ), 6.60 (1H, s, ), 6.88 (1H, s, ), 7.08-7.28 (4H, m).

Primjer 16 Example 16

cis-5-5a,6,-10b-Tetrahidro-metilindeno[2,1-b]indol cis-5-5a,6,-10b-Tetrahydro-methylindeno[2,1-b]indole

Smjesa 0.6 g (0.00289 mol) 5,5a,6,10b-tetrahidroindeno[2,1-b]indola, 0.9 g (0.00723 mol) K2CO3 i 1.03 g(0.00723 mol) metil jodida u 10 ml acetonitrila miješana je preko noći na sobnoj temperaturi. Dobivena smjesa je filtrirana i isparavana. Dobiveni ostatak je otopljen u eteru i 2 puta ispran s vodom. Sušenje (Na2SO4) i isparavanje su dali 0.25 g (39%) naslovnog spoja. A mixture of 0.6 g (0.00289 mol) 5,5a,6,10b-tetrahydroindeno[2,1-b]indole, 0.9 g (0.00723 mol) K2CO3 and 1.03 g (0.00723 mol) methyl iodide in 10 ml acetonitrile was stirred overnight at room temperature. The resulting mixture was filtered and evaporated. The resulting residue was dissolved in ether and washed twice with water. Drying (Na2SO4) and evaporation gave 0.25 g (39%) of the title compound.

1H NMR (CDCl3), δ : 2.78 (3H, s,), 3.2 (2H, d,), 4.3 (1H, m,), 4.66 (1H, d,), 6.37 (1H, d,), 6.68 (1H, t,), 7.06 (1H, t), 7.13-7.18 (2H, m,), 7.22-7.26 (1H, m,), 7.3-7.37 (2H, m,). 1H NMR (CDCl3), δ : 2.78 (3H, s,), 3.2 (2H, d,), 4.3 (1H, m,), 4.66 (1H, d,), 6.37 (1H, d,), 6.68 ( 1H, t), 7.06 (1H, t), 7.13-7.18 (2H, m), 7.22-7.26 (1H, m), 7.3-7.37 (2H, m).

Primjer 17 Example 17

Otopini 5.0 g (0.020 mol) 5,10-dihidro-8-metoksi-6-metilindeno[1,2-b]indola u 50 ml THF dodano je 8.1 g (0.080 mol) morfolino borana i, u kapima, 6.3 ml konc. klorovodikove kiseline. U početku egzotermna reakcijska smjesa miješana je na sobnoj temperaturi tokom 72 sata. Dodano je još 6.3 ml konc. klorovodikove kiseline, pa je smjesa miješana preko noći. Zatim je dodano 25 ml vode i 5 ml konc. klorovodikove kiseline, pa je smjesa zagrijavana dok se nije otopio najveći dio krutog materijala. Otopina je zatim filtrirana na vruće i filtrat je ohlađen i alkaliziran dodatkom 10 M otopine natrijevog hidroksida. Filtriranje i ispiranje vodom dali su 1.93 g (38.4%) naslovnog spoja. 8.1 g (0.080 mol) morpholino borane and, dropwise, 6.3 ml conc. . hydrochloric acid. Initially, the exothermic reaction mixture was stirred at room temperature for 72 hours. Another 6.3 ml of conc. hydrochloric acid, and the mixture was stirred overnight. Then 25 ml of water and 5 ml of conc. of hydrochloric acid, and the mixture was heated until most of the solid material was dissolved. The solution was then filtered while hot and the filtrate was cooled and made alkaline by addition of 10 M sodium hydroxide solution. Filtration and washing with water gave 1.93 g (38.4%) of the title compound.

1H NMR (CDCl3) : δ : 2.08 (3H, s,), 3.15-3.25 (1H, dd,), 3.42-3.55 (1H, dd,), 3.7 (3H, s,), 4.1-4.22 (1H, t,), 5.22-5.28 (1H, d,), 6.42-6.46 (1H, d), 6.6-6.65 (1H, d,), 7.14-7.25 (3H, m,), 7.3-7.4 (1H, m,). 1H NMR (CDCl3): δ: 2.08 (3H, s,), 3.15-3.25 (1H, dd,), 3.42-3.55 (1H, dd,), 3.7 (3H, s,), 4.1-4.22 (1H, t,), 5.22-5.28 (1H, d,), 6.42-6.46 (1H, d), 6.6-6.65 (1H, d,), 7.14-7.25 (3H, m,), 7.3-7.4 (1H, m ,).

Primjer 18 Example 18

Otopini 0.8 g (0.3 mmol) 5,10-dihidro-8-metoksi-7,9-dimetilindeno[1,2-b]indola i 1.21 g morfolino borana u 4 ml dioksana u kapima je dodan 1 ml konc. klorovodikove kiseline. Smjesa je refluksirana tokom 30 minuta, ohlađena je i dodano je 3 ml 6M klorovodikove kiseline. Dobivena smjesa je zatim refluksirana 15 minuta. Nakon hlađenja, otopina je alkalizirana s vodenom otopinom natrijevog hidroksida i ekstrahirana tri puta s eterom. Sušenje (MgSO4) i isparavanje dali su sirov proizvod koji je kristaliziran otapanjem u etil acetatu i dodavanjem lakog petrol etera na -20°. 1 ml conc. was added dropwise to a solution of 0.8 g (0.3 mmol) of 5,10-dihydro-8-methoxy-7,9-dimethylindeno[1,2-b]indole and 1.21 g of morpholino borane in 4 ml of dioxane. hydrochloric acid. The mixture was refluxed for 30 minutes, cooled and 3 ml of 6M hydrochloric acid was added. The resulting mixture was then refluxed for 15 minutes. After cooling, the solution was basified with aqueous sodium hydroxide and extracted three times with ether. Drying (MgSO4) and evaporation gave the crude product which was crystallized by dissolving in ethyl acetate and adding light petroleum ether at -20°.

Filtriranje je dalo 0.73 g (92%) naslovnog spoja: 1 H Filtration gave 0.73 g (92%) of the title compound: 1H

Primjer 19 Example 19

cis-4b,5,9b,10-Tetrahidro-6-izopropilindeno[1,2-b]indol cis-4b,5,9b,10-Tetrahydro-6-isopropylindeno[1,2-b]indole

Otopini 4.95 g (0.020 mol) 5,10-dihidro-6-izopropilindeno[1,2-b]indola i 8.08 g (0.080 mol) morfolino borana u 25 ml dioksana dodano je u kapima 7 ml konc. klorovodikove kiseline. Smjesa je refluksirana 30 minuta, ohlađena do sobne temperature i zatim joj je dodano 20 ml 6M klorovodikove kiseline. Smjesa je refluksirana tokom 15 minuta. Nakon hlađenja, smjesa je alkalizirana dodatkom vodene otopine natrijevog hidroksida i ekstrahirana je tri puta s eterom. Sušenjem (MgSO4) i isparavanje dali su sirov proizvod koji je prečišćen kromatografijom na koloni silikagela uz korištenje metilen klorid/lakog petrol etera (20/80) kao eluenta. A solution of 4.95 g (0.020 mol) of 5,10-dihydro-6-isopropylindeno[1,2-b]indole and 8.08 g (0.080 mol) of morpholino borane in 25 ml of dioxane was added dropwise to 7 ml conc. hydrochloric acid. The mixture was refluxed for 30 minutes, cooled to room temperature and then 20 ml of 6M hydrochloric acid was added to it. The mixture was refluxed for 15 minutes. After cooling, the mixture was made alkaline by the addition of aqueous sodium hydroxide solution and extracted three times with ether. Drying (MgSO4) and evaporation gave the crude product which was purified by silica gel column chromatography using methylene chloride/light petroleum ether (20/80) as eluent.

Tako je dobiveno 3.53 g (71%) naslovnog spoja. Thus, 3.53 g (71%) of the title compound were obtained.

1H NMR (CDCl3), δ : 1.19 (3H, d,), 1.29 (3H, d,), 2.84 (1h, dq, 3,26 (1H, dd), 3.56 (1H, dd,), 4.24 (1H, td,), 5.31 (1H, d,), 6.79 (1H, dd), 7.05-7.09 (1H, m,), 7.28-7.21 (3H, m,), 7.36-7.40 (1H, m,). 1H NMR (CDCl3), δ : 1.19 (3H, d,), 1.29 (3H, d,), 2.84 (1h, dq, 3.26 (1H, dd), 3.56 (1H, dd,), 4.24 (1H , td ), 5.31 (1H, d ), 6.79 (1H, dd), 7.05-7.09 (1H, m ), 7.28-7.21 (3H, m ), 7.36-7.40 (1H, m ).

Primjer 20 Example 20

Balon sušen na plamenu napunjen je, pod inertnom atmosferom, sa 4b,5,9b,10-tetrahidroindeno[1,2-b]indolom (1.04 g, 5.02 mmol) i svježe destiliranim THF (30 cm3). Otopina je ohlađena na -78°C i dodana je otopina n-butillitija (3.45 cm3 1.6M otopine u heksanu, 1.1 ekvivalent), u kapima. Blijedo žuta otopina ostavljena je da se zagrije do sobne temperature pa je propuhavan suhi gasoviti ugljen dioksid sve dok se otopina nije obezbojila. Otapalo i višak ugljen dioksida su pažljivo uklonjeni vakuumskom pumpom pod smanjenim tlakom, pa je ponovno uspostavljena inertna atmosfera suhog dušika. Bezbojna kruta supstancija je ponovo otopljena u suhom THF (30 cm3), ohlađena do -78°C, pa je dodan još 1.1 ekvivalent n-butillitija. Reakcijska smjesa je miješana na -78°C tokom 90 minuta i reakcija je prekinuta sa jodometanom (0.35 cm3, 1.2 ekvivalenta). Nakon zagrijavanja reakcijske smjese do sobne temperature otapala su uklonjena kao i prvi put, pa je dodana 2M otopina HC1 (20 cm3). A flame-dried flask was charged, under an inert atmosphere, with 4b,5,9b,10-tetrahydroindeno[1,2-b]indole (1.04 g, 5.02 mmol) and freshly distilled THF (30 cm3). The solution was cooled to -78°C and a solution of n-butyllithium (3.45 cm3 of a 1.6M solution in hexane, 1.1 equivalent) was added dropwise. The pale yellow solution was allowed to warm to room temperature and dry carbon dioxide gas was bubbled through until the solution became colorless. The solvent and excess carbon dioxide were carefully removed with a vacuum pump under reduced pressure, and an inert atmosphere of dry nitrogen was re-established. The colorless solid was redissolved in dry THF (30 cm3), cooled to -78°C, and another 1.1 equivalent of n-butyllithium was added. The reaction mixture was stirred at -78°C for 90 minutes and quenched with iodomethane (0.35 cm3, 1.2 equivalents). After heating the reaction mixture to room temperature, the solvents were removed as the first time, and a 2M solution of HC1 (20 cm3) was added.

Nakon što je prestalo izdvajanje plina (oko 20 minuta), otopina je neutralizirana s krutim natrijevim karbonatom. Organski materijal je ekstrahiran s etil acetatom, pa je ekstrakt ispran slanom otopinom i sušen (Na2SO4). Nakon uklanjanja otapala, proizvod je pročišćen fleš-kromatografijom [ Rf =0.4 (10%-EtOAc/petrol eter 60-80°C)], uz eluiranje s 5% etil acetat/petrol eterom (60-80°C) i dobiveno je bezbojno ulje koje se na -20°C ukrutilo da bi dalo roza krutu supstanciju. Doprinos: 0.76 g, 69% M.p. 52°C; After gas evolution stopped (about 20 minutes), the solution was neutralized with solid sodium carbonate. The organic material was extracted with ethyl acetate, and the extract was washed with brine and dried (Na2SO4). After removing the solvent, the product was purified by flash chromatography [Rf =0.4 (10%-EtOAc/petroleum ether 60-80°C)], eluting with 5% ethyl acetate/petroleum ether (60-80°C) and obtained a colorless oil which solidified at -20°C to give a pink solid. Contribution: 0.76 g, 69% M.p. 52°C;

1H NMR (CDCl3), δ : 7.3-7.1 (5H, m); 6.96 (1H, ddd); 6.70 (1H, ddd); 6.53 (1H,d,J=7.7Hz), 4.2 (1H,br), 3.37 (1H,dm,J=8.2Hz), 3.48 (1H,dd,J=16.3,7.2Hz), 3.14 (1H,dd,J=16.3,2.0Hz), 1.61 (3H,s). 1H NMR (CDCl3), δ: 7.3-7.1 (5H, m); 6.96 (1H, ddd); 6.70 (1H, ddd); 6.53 (1H,d,J=7.7Hz), 4.2 (1H,br), 3.37 (1H,dm,J=8.2Hz), 3.48 (1H,dd,J=16.3,7.2Hz), 3.14 (1H,dd ,J=16.3,2.0Hz), 1.61 (3H,s).

Primjer 21 Example 21

cis-4b,5,9b,10-Tetrahidro-4b-metil-8-izopropilindeno[1,2-b]indol cis-4b,5,9b,10-Tetrahydro-4b-methyl-8-isopropylindeno[1,2-b]indole

Pod inertnom atmosferom, balon sušen na plamenu je napunjen 4b,5,9b,10-tetrahidro-8-izopropilindeno[1,2-b]indolom (1.49 g, 5.98 mmol) i suhim THF (20 cm3). Otopina je ohlađena na -78°C i u kapima je dodana otopina n-butillitija u heksanu (4.0 cm3 1.6 M otopine). Reakcija je zagrijana do sobne temperature, pa je suhi plinoviti CO2 propuhavan sve dok nije nestala boja aniona. Otapalo i višak CO2 pažljivo su uklonjeni vakuumskom pumpom, dobivena kruta supstancija ponovo je otopljena u suhom THF (20 cm3), pa je ohlađena na -78°C. Dodan je i ekvivalent n-butillitija, te je reakcijska smjesa miješana 30 minuta na -20°C. Na -78°C dodan je jodometan (0.4 cm3), 1 ekvivalent), pa je reakcijska smjesa zagrijana na sobnu temperaturu i miješana 3 sata. Otapala su uklonjena vakuumskom pumpom, te je dodana 2N otopina HCl (20 cm3). Nakon 20 minuta otopina je alkalizirana acetatom. organski ekstrakt ispran je slanom otopinom, sušen (Na2SO4) i koncentriran pod vakuumom. Proizvod je pročišćen fleš-kromatografijom kao nestabilno blijedo žuto ulje. Doprinos: 1.01 g, 64% 1H NMR (CDCl3), δ : 7.30-7.15 (4H, m), 7.00 (1H, s) 6.85 (1H, d, J=7.9Hz), 6.49 (1H, d, J=7.9Hz), 4.0 (1H, br), 3.73 (1H, d, J=8.1Hz), 3.49 (1H, dd, J=16.1, 8.2Hz), 3.16 (1H, d, J=16.1Hz), 2.79 (1H, septet, J=6.8Hz), 1.61 (3H, s), 1.19 (6H, d, J=6.8Hz). Under an inert atmosphere, a flame-dried flask was charged with 4b,5,9b,10-tetrahydro-8-isopropylindeno[1,2-b]indole (1.49 g, 5.98 mmol) and dry THF (20 cm3). The solution was cooled to -78°C and a solution of n-butyllithium in hexane (4.0 cm3 of 1.6 M solution) was added dropwise. The reaction was warmed to room temperature, and dry gaseous CO2 was blown in until the color of the anion disappeared. The solvent and excess CO2 were carefully removed with a vacuum pump, the resulting solid was redissolved in dry THF (20 cm3) and cooled to -78°C. An equivalent of n-butyllithium was added, and the reaction mixture was stirred for 30 minutes at -20°C. At -78°C, iodomethane (0.4 cm3, 1 equivalent) was added, and the reaction mixture was warmed to room temperature and stirred for 3 hours. Solvents were removed with a vacuum pump, and 2N HCl solution (20 cm3) was added. After 20 minutes, the solution was alkalized with acetate. the organic extract was washed with brine, dried (Na2SO4) and concentrated under vacuum. The product was purified by flash chromatography as an unstable pale yellow oil. Yield: 1.01 g, 64% 1H NMR (CDCl3), δ : 7.30-7.15 (4H, m), 7.00 (1H, s) 6.85 (1H, d, J=7.9Hz), 6.49 (1H, d, J= 7.9Hz), 4.0 (1H, br), 3.73 (1H, d, J=8.1Hz), 3.49 (1H, dd, J=16.1, 8.2Hz), 3.16 (1H, d, J=16.1Hz), 2.79 (1H, septet, J=6.8Hz), 1.61 (3H, s), 1.19 (6H, d, J=6.8Hz).

Primjer 22 Example 22

Pod uvjetima bez vode, 4b,5,9b,10-tetrahidro-2-metoksi-1,3-dimetilindeno[1,2-b]indol (76 mg, 0.29 mmol) otopljen je u suhom diklorometanu (DCM, 1 cm3) u koji je dodana mala količina etanola. Otopina je ohlađena na -78°C i dodana je otopina bor tribromida u DCM (0.5 cm3 1M otopine). Reakcijska smjesa je polako zagrijana do sobne temperature, pri čemu se reakcija javila na oko 0°C. Nakon 30 minuta na 10°C oprezno je dodana voda (1 cm3), te je smjesa miješana 15 minuta. Pretežno krut materijal iscrpno je ekstrahiran između DCM i zasićene otopine natrijevog bikarbonata. DCM sloj sušen je (Na2SO4) i filtriran kroz jastučić silikagela za fleš-kromatografiju da bi dao bezbojnu krutu supstanciju. Doprinos: 73 mg, 100%. T.t. 178-180°C (rasp.). Under water-free conditions, 4b,5,9b,10-tetrahydro-2-methoxy-1,3-dimethylindeno[1,2-b]indole (76 mg, 0.29 mmol) was dissolved in dry dichloromethane (DCM, 1 cm3) to which a small amount of ethanol was added. The solution was cooled to -78°C and a solution of boron tribromide in DCM (0.5 cm3 of 1M solution) was added. The reaction mixture was slowly warmed to room temperature, whereby the reaction occurred at about 0°C. After 30 minutes at 10°C, water (1 cm3) was cautiously added, and the mixture was stirred for 15 minutes. The mostly solid material was exhaustively extracted between DCM and saturated sodium bicarbonate solution. The DCM layer was dried (Na 2 SO 4 ) and filtered through a flash silica gel pad to give a colorless solid. Contribution: 73 mg, 100%. T.t. 178-180°C (disp.).

1H NMR (CDCl3), δ : 7.16 (1H, d, J=7.3Hz,), 6.99 (1H, ddm), 6.94 (1H, s), 6.73 (1H, ddm, J=7.3, 1.1Hz), 6.60 (1H, d, J=7.7Hz), 5.20 (1H, d, J=8.4), 4.4 (2H, br), 4.15 (1H, ddm), 3.38 (1H, dd, J=16.1, 8.3Hz), 3.09 (1H, dd, J=16.2Hz), 2.21 (3H, s), 2.12 (3H, s). 1H NMR (CDCl3), δ : 7.16 (1H, d, J=7.3Hz,), 6.99 (1H, ddm), 6.94 (1H, s), 6.73 (1H, ddm, J=7.3, 1.1Hz), 6.60 (1H, d, J=7.7Hz), 5.20 (1H, d, J=8.4), 4.4 (2H, br), 4.15 (1H, ddm), 3.38 (1H, dd, J=16.1, 8.3Hz), 3.09 (1H, dd, J=16.2Hz), 2.21 (3H, s), 2.12 (3H, s).

Primjer 23 Example 23

cis-5-Acetil-4b,5,9b,10-tetrahidro-2-metoksi-1,3-dimetilindeno[1,2-b]indol cis-5-Acetyl-4b,5,9b,10-tetrahydro-2-methoxy-1,3-dimethylindeno[1,2-b]indole

4b,5,9b,10- tetrahidro-2-metoksi-1,3-dimetilindeno[1,2-b]indol (140 mg, 0.53 mmol) miješan je u anhidridu octene kiseline (2 cm3) tokom 5 minuta. Zatim je dodana voda (5 cm3) i miješanje je nastavljeno još 30 minuta. Otopina je neutralizirana s krutim natrijevim bikarbonatom, te je ekstrahirana diklorometanom. Organski materijal je sušen (MgSO4), koncentriran, pa je višak diklorometana azeotropno uklonjen na rotacijskom isparivaču uz korištenje petrol etera (60-80°C), da bi se dobila bezbojna kruta supstancija. Doprinos: 170 mg, 100%. T.t. 200°C. 4b,5,9b,10-tetrahydro-2-methoxy-1,3-dimethylindeno[1,2-b]indole (140 mg, 0.53 mmol) was stirred in acetic anhydride (2 cm3) for 5 minutes. Then water (5 cm3) was added and stirring was continued for another 30 minutes. The solution was neutralized with solid sodium bicarbonate and extracted with dichloromethane. The organic material was dried (MgSO4), concentrated, and excess dichloromethane was azeotropically removed on a rotary evaporator using petroleum ether (60-80°C) to obtain a colorless solid. Contribution: 170 mg, 100%. T.t. 200°C.

1H NMR (CDCl3), δ : (mixture of E/Z isomers). 8.10 (1/2H, d, J=7.9 Hz), 8/4-7.0 (4 1/2H, m), 6.24 and 5.75 (1H, d, J=8.2 and 7.7Hz) 4.23 and 4.13 (1H, ddd, J=7.5 and 8.3Hz), 3.64 (3H, s), 3.4 (1H, m), 3.13 (1H, 2 x dd, J=15.5Hz), 2.59 and 2.50 (3H, s), 2.53 and 2.22 (3H, s), 2.16 and 2.14 (3H, s). 1H NMR (CDCl3), δ: (mixture of E/Z isomers). 8.10 (1/2H, d, J=7.9 Hz), 8/4-7.0 (4 1/2H, m), 6.24 and 5.75 (1H, d, J=8.2 and 7.7Hz) 4.23 and 4.13 (1H, ddd , J=7.5 and 8.3Hz), 3.64 (3H, s), 3.4 (1H, m), 3.13 (1H, 2 x dd, J=15.5Hz), 2.59 and 2.50 (3H, s), 2.53 and 2.22 ( 3H, s), 2.16 and 2.14 (3H, s).

Primjer 24 Example 24

cis-5-Acetil-4b,5,9b,10-tetrahidro-2-hidroksi-1,3-dimetilindeno[1,2-b]indol cis-5-Acetyl-4b,5,9b,10-tetrahydro-2-hydroxy-1,3-dimethylindeno[1,2-b]indole

Pod uvjetima bez vode, otopina 5-acetil-4b,5,9b,10-tetrahidro-2-hidroksi-1,3-dimetilindeno[1,2-b]indola (109 mg, 0.35 mmol) u diklorometanu (1 cm3) ohlađena je na -78°C, joj je dodana otopina bor tribromida u diklorometanu (0.7 cm3 1M otopine). Smjesa je ostavljena da se zagrije do sobne temperature i miješana je 90 minuta, nakon čega je pažljivo dodana voda (5 cm3). Nakon još 10 minuta miješanja smjesa je razblažena i ekstrahirana sa diklorometanom. Kombinirani diklorometanski ekstrakti su sušeni (Na2SO4) i filtrirani kroz jastučić silikagela za fleš-kromatografiju, uz daljnje eluiranje s 30% EtOAc/petrol eterom 60-80°C. Uklanjanje otapala dalo je bezbojnu krutu supstanciju. Doprinos: 96 mg, 94%. T.t. 205°C (raspad). Under water-free conditions, a solution of 5-acetyl-4b,5,9b,10-tetrahydro-2-hydroxy-1,3-dimethylindeno[1,2-b]indole (109 mg, 0.35 mmol) in dichloromethane (1 cm3) it was cooled to -78°C, a solution of boron tribromide in dichloromethane (0.7 cm3 of 1M solution) was added to it. The mixture was allowed to warm to room temperature and stirred for 90 minutes, after which water (5 cm3) was carefully added. After another 10 minutes of mixing, the mixture was diluted and extracted with dichloromethane. The combined dichloromethane extracts were dried (Na2SO4) and filtered through a pad of silica gel for flash chromatography, further eluting with 30% EtOAc/petroleum ether 60-80°C. Removal of the solvent gave a colorless solid. Contribution: 96 mg, 94%. T.t. 205°C (decomposition).

1H NMR (CDCl3), δ : (mixture of E/Z isomers). 8.06 (1/2H, d, J=7.1 Hz), 8.05-7.00 (4 1/2H, m), 4.23 and 5.75 (1H, d, J=8.1 and 7.5Hz) 4.6 (1H, br), 4.22-4.08 (1H, 2 x ddd), 3.45-3.26 (1H, m), 3.25-3.05 (1H, 2 x dd), 2.63 and 2.52 (3H, s), 2.20 and 2.17 (3H, s), 2.13 and 2.11 (3H, s). 1H NMR (CDCl3), δ: (mixture of E/Z isomers). 8.06 (1/2H, d, J=7.1 Hz), 8.05-7.00 (4 1/2H, m), 4.23 and 5.75 (1H, d, J=8.1 and 7.5Hz) 4.6 (1H, br), 4.22- 4.08 (1H, 2 x ddd), 3.45-3.26 (1H, m), 3.25-3.05 (1H, 2 x dd), 2.63 and 2.52 (3H, s), 2.20 and 2.17 (3H, s), 2.13 and 2.11 (3H, s).

Primjer 25 Example 25

5,10-Dihidro-2-metoksi-1,3-dimetil-8-izopropilindeno[1,2-b]indol (1.68 g, 5.5 mmol) otopljen je u triflorooctenoj kiselini (10 cm3) i jako miješan. Dodan je trietilsilan (1 cm3, 1.1 ekvivalent) i miješanje je nastavljeno još 4 sata. Reakcijska smjesa je prosuta u vodu, miješana 15 minuta i neutralizirana sa 1M NaOH. Cijeli organski materijal ekstrahiran je etil acetatom, ispran vodom i sušen (Na2SO4). Nakon isparavanja otapala, kruti je materijal prekristaliziran iz petrol etera (60-80°C) u obliku bijelih iglica. Doprinos: 1.18 g, 70%. T.t. 106°C. 5,10-Dihydro-2-methoxy-1,3-dimethyl-8-isopropylindeno[1,2-b]indole (1.68 g, 5.5 mmol) was dissolved in trifluoroacetic acid (10 cm3) and stirred vigorously. Triethylsilane (1 cm 3 , 1.1 equivalent) was added and stirring was continued for another 4 hours. The reaction mixture was poured into water, stirred for 15 minutes and neutralized with 1M NaOH. The whole organic material was extracted with ethyl acetate, washed with water and dried (Na2SO4). After evaporation of the solvent, the solid material was recrystallized from petroleum ether (60-80°C) in the form of white needles. Contribution: 1.18 g, 70%. T.t. 106°C.

1H NMR (CDCl3), δ : 7.05 (1H, s), 6.97 (1H, s), 6.88 (1H, dd, J=8.6Hz), 6.55 (1H, d, J=8.1Hz), 5.19 (1H, d, J=8.4Hz), 4.18 (1H, ddd), 3.8 (1H, br), 3.64 (3H, s), 3.36 (1H, dd, J=16.5, 8.3Hz), 3.07 (1H, d(br) J=16.5Hz), 2.81 (1H, dd, J=7.0Hz), 2.25 (3H, s), 2.15 (3H, s), 1.20 (6H, d, J=7.0Hz). 1H NMR (CDCl3), δ : 7.05 (1H, s), 6.97 (1H, s), 6.88 (1H, dd, J=8.6Hz), 6.55 (1H, d, J=8.1Hz), 5.19 (1H, d, J=8.4Hz), 4.18 (1H, ddd), 3.8 (1H, br), 3.64 (3H, s), 3.36 (1H, dd, J=16.5, 8.3Hz), 3.07 (1H, d(br ) J=16.5Hz), 2.81 (1H, dd, J=7.0Hz), 2.25 (3H, s), 2.15 (3H, s), 1.20 (6H, d, J=7.0Hz).

Primjer 26 Example 26

Otopina 4b,5,9b,10-tetrahidro-2-hidroksi-1,3-dimetil-8-izopropilindeno[1,2-b]indola (97 mg, 0.32 mmol) u diklorometanu (DCM, 1 cm3) kojoj je dodano nekoliko pare etanola, ohlađena je na -78°C. Dodan je bor tribromid (0.4 cm3, 1M otopina u DCM), pa je reakcijska smjesa zagrijana do sobne temperature. Oprezno je dodana voda a (1 cm3), pa je smjesa podijeljena između DCM i otopine natrijevog bikarbonata. organski sloj je sušen (Na2SO4) i filtriran kroz jastučić silikagela za fleš-kromatografiju, uz eluiranje sa DCM. Uklanjanje otapala dalo je bijelu krutu supstanciju. Doprinos: 1.18 g, 70%. T.t. 106°C. A solution of 4b,5,9b,10-tetrahydro-2-hydroxy-1,3-dimethyl-8-isopropylindeno[1,2-b]indole (97 mg, 0.32 mmol) in dichloromethane (DCM, 1 cm3) was added several vapors of ethanol, it was cooled to -78°C. Boron tribromide (0.4 cm3, 1M solution in DCM) was added, and the reaction mixture was warmed to room temperature. Water a (1 cm3) was cautiously added, and the mixture was partitioned between DCM and sodium bicarbonate solution. the organic layer was dried (Na2SO4) and filtered through a flash silica gel pad, eluting with DCM. Removal of the solvent gave a white solid. Contribution: 1.18 g, 70%. T.t. 106°C.

1H NMR (CDCl3), δ : 7.04 (1H, s) 6.95 (1H, s), 6.87 (1H, dd), 6.56 (1H, d, J=8.1Hz), 5.20 (1H, d, J=8.6Hz), 4.16 (1H, ddm), 4.6-4.0 (2H, br), 3.36 (1H, dd), 3.06 (1H, dd), 2.81 (1H, septet, J=7.0Hz) 2.20 (3H, s), 2.12 (3H, s), 1.19 (6H, d, J=7.9Hz). 1H NMR (CDCl3), δ : 7.04 (1H, s) 6.95 (1H, s), 6.87 (1H, dd), 6.56 (1H, d, J=8.1Hz), 5.20 (1H, d, J=8.6Hz ), 4.16 (1H, ddm), 4.6-4.0 (2H, br), 3.36 (1H, dd), 3.06 (1H, dd), 2.81 (1H, septet, J=7.0Hz) 2.20 (3H, s), 2.12 (3H, s), 1.19 (6H, d, J=7.9Hz).

Primjer 27 Example 27

5,10-Dihidro-2,8-dimetoksi-1,3-dimetilindeno[1,2-b]indol (1.04 g, 3.55 mmol) je otopljen u trifluorooctenoj kiselini (5 cm3) i uz jako miješanje dodat je trimetilsilan (0.6 cm3). Miješanje je nastavljeno 4 sata, te je reakcija nepotpuno završena, što se vidi na osnovi nečistoća koje su prisutne na TLC. Otopina je prosuta u vodu, miješana, te je namještena na pH 7.0 dodavanjem krutog natrijevog bikarbonata. organski materijal je ekstrahiran sa DCM koji je ispran otopinom natrijevog bikarbonata, pa je filtriran kroz filtar papir za odvajanje faza. Proizvod i početni materijal su razdvojeni kromatografijom na koloni, uz eluiranje sa 20% EtOAc/petro eterom 60-80°C, da bi se dobio početni indol (0.06 g, 6%) i bezbojnu krutu supstanciju. Doprinos: 0.57 g, 58%. T.t. 149-50°C (iz EtOAc/petrol etera). 5,10-Dihydro-2,8-dimethoxy-1,3-dimethylindeno[1,2-b]indole (1.04 g, 3.55 mmol) was dissolved in trifluoroacetic acid (5 cm3) and trimethylsilane (0.6 cm3). Stirring was continued for 4 hours, and the reaction was incomplete, as evidenced by impurities present on TLC. The solution was poured into water, mixed, and adjusted to pH 7.0 by adding solid sodium bicarbonate. organic material was extracted with DCM washed with sodium bicarbonate solution and filtered through filter paper for phase separation. The product and starting material were separated by column chromatography, eluting with 20% EtOAc/petro ether 60-80°C, to give the starting indole (0.06 g, 6%) and a colorless solid. Contribution: 0.57 g, 58%. T.t. 149-50°C (from EtOAc/petroleum ether).

1H NMR (CDCl3), δ : 6.99 (1H, s), 6.79 (1H, m), 6.57 (2H, m), 5.18 (1H, d, J=8.5Hz), 4.18 (1H, dd(br)), 3.74 (3H, s), 3.65 (3H, s), 3.35 (1H, dd, 3J=8.4Hz), 3.06 (1H, d(d)), 2.25 (3H, s), 2.15 (3H, s). 1H NMR (CDCl3), δ : 6.99 (1H, s), 6.79 (1H, m), 6.57 (2H, m), 5.18 (1H, d, J=8.5Hz), 4.18 (1H, dd(br)) , 3.74 (3H, s), 3.65 (3H, s), 3.35 (1H, dd, 3J=8.4Hz), 3.06 (1H, d(d)), 2.25 (3H, s), 2.15 (3H, s) .

Primjer 28 Example 28

cis-5-Acetil-4b,5,9b,10-tetrahidro-4b,9b-dimentilindeno[1,2-b]indol cis-5-Acetyl-4b,5,9b,10-tetrahydro-4b,9b-dimentylindeno[1,2-b]indole

4b,5,9b,10-Tetrahidro-4b,9b-dimentilindeno[1,2-b]indol (0.2 g, 0.85 mmol) je otopljen u anhidridu octene kiseline (1 cm3) i otopina je miješana na sobnoj temperaturi tokom 16 sati. Reakcijska smjesa je prosuta u zasićenu otopinu natrijevog bikarbonata i miješana još pola sata. Smjesa je zatim ekstrahirana s eterom (3 x 15 cm3) i kombinirani organski ekstrakti su prikupljeni i isprani slanom otopinom, sušeni (Na2SO4) i isparavani da bi dali naslovni spoj kao ulje. Ulje je pročišćeno fleš-kromatografijom na silikagelu uz eluiranja s 5-7% etil acetat/60-80°C petrol eterom, da bi se dobila bezbojna kruta supstancija. Doprinos: 0.15 g, 64%. M.p. 81°C. 4b,5,9b,10-Tetrahydro-4b,9b-dimentylindeno[1,2-b]indole (0.2 g, 0.85 mmol) was dissolved in acetic anhydride (1 cm3) and the solution was stirred at room temperature for 16 hours. . The reaction mixture was poured into a saturated sodium bicarbonate solution and stirred for another half hour. The mixture was then extracted with ether (3 x 15 cm 3 ) and the combined organic extracts were collected and washed with brine, dried (Na 2 SO 4 ) and evaporated to give the title compound as an oil. The oil was purified by flash chromatography on silica gel, eluting with 5-7% ethyl acetate/60-80°C petroleum ether, to obtain a colorless solid. Contribution: 0.15 g, 64%. MP 81°C.

1H NMR (CDCl3), δ : 7.82 (1H, s), 6.99-7.29 (7H, m), 3.26 (1H, d, J=15.9Hz), 2.97 (1H, d, J=15.9Hz), 2.42 (3H, s), 1.77 (3H, s), 1.25 (3H, s). 1H NMR (CDCl3), δ : 7.82 (1H, s), 6.99-7.29 (7H, m), 3.26 (1H, d, J=15.9Hz), 2.97 (1H, d, J=15.9Hz), 2.42 ( 3H, s), 1.77 (3H, s), 1.25 (3H, s).

Primjer 29 Example 29

cis-4b,5,9b,10-Tetrahidro-4b,8,9b-trimetilindeno[1,2-b]indol cis-4b,5,9b,10-Tetrahydro-4b,8,9b-trimethylindeno[1,2-b]indole

Otopina 9b,10-dihidro-8,9b-dimetilindeno[1,2-b]indola (5.05 g, 0.022 mol) u suhom tetrahidrofuranu (100 cm3) na -78°C, unesenom u balon sušen na plamenu pod atmosferom dušika, u kapima je dodan metilitij (1.4M otopina u dietil eteru, 23.2 cm3, 0.032 mol). Smjesa je miješana na -78°C tokom 2 sata i zatim na -15°C još 1 sat. Zatim je dodana zasićena otopina amonijevog klorida (3 cm3) i smjesa je ostavljena da se zagrije do sobne temperature. Reakcijska smjesa je podijeljena između etera i zasićene otopine amonijevog klorida, pa su slojevi odvojeni. Vodena faza je ekstrahirana sa dietil eterom (2 x 25 cm3) pa su kombinirani organski ekstrakti isprani slanom otopinom, sušeni (Na2SO4) i isparavani da bi dali naslovni spoj kao bijeličastu krutu supstanciju. Ova supstancija je pročišćena fleš-kromatografijom na silikagelu, uz eluiranje sa 3-10% etil acetat/petrol eterom (60-80°C), da bi dala bezbojnu krutu supstanciju. Doprinos: 2.73 g, 51%. T.t. 208-212°C. A solution of 9b,10-dihydro-8,9b-dimethylindeno[1,2-b]indole (5.05 g, 0.022 mol) in dry tetrahydrofuran (100 cm3) at -78°C, placed in a flame-dried flask under a nitrogen atmosphere, methyllithium (1.4M solution in diethyl ether, 23.2 cm3, 0.032 mol) was added dropwise. The mixture was stirred at -78°C for 2 hours and then at -15°C for another 1 hour. Saturated ammonium chloride solution (3 cm 3 ) was then added and the mixture was allowed to warm to room temperature. The reaction mixture was partitioned between ether and saturated ammonium chloride solution, and the layers were separated. The aqueous phase was extracted with diethyl ether (2 x 25 cm3) and the combined organic extracts were washed with brine, dried (Na2SO4) and evaporated to give the title compound as an off-white solid. This substance was purified by flash chromatography on silica gel, eluting with 3-10% ethyl acetate/petroleum ether (60-80°C), to give a colorless solid. Contribution: 2.73 g, 51%. T.t. 208-212°C.

1H NMR (CDCl3), δ : 7.1-7.3 (4H, m), 6.94 (1H, m,), 6.77 (1H, d, J=7.8Hz), 6.46 (1H, d, J=7.8Hz), 3.35 (1H, d, J=15.9Hz), 3.06 (1H, d, J=15.9Hz), 2.22 (3H, s), 1.46 (3h, s), 1.34 (3H, s). 1H NMR (CDCl3), δ: 7.1-7.3 (4H, m), 6.94 (1H, m,), 6.77 (1H, d, J=7.8Hz), 6.46 (1H, d, J=7.8Hz), 3.35 (1H, d, J=15.9Hz), 3.06 (1H, d, J=15.9Hz), 2.22 (3H, s), 1.46 (3h, s), 1.34 (3H, s).

Primjer 30 Example 30

cis-4b,5,9b,10-Tetrahidro-4b,9b-dimetil-8-izopropilindeno[1,2-b]indol cis-4b,5,9b,10-Tetrahydro-4b,9b-dimethyl-8-isopropylindeno[1,2-b]indole

Otopini metillitija (1.4 M u eteru, 14.5 cm3, 12.4 mmol) u suhom THF (20 cm3) na -78°C pod atmosferom dušika, u balonu sušenom na plamenu, u kapima je, tokom 1 sat, dodana otopina 9b,10-dihidro-9b-metil-8-izopropilindeno[1,2-b]indola (1.62 g, 6.20 mmol) u suhom THF (30 cm3). Nakon dodavanja, smjesa je miješana još pola sata na -78°C. Zatim je dodana zasićena otopina amonijevog klorida (2 cm3), pa je smjesa ostavljena da se zagrije do sobne temperature. Reakcijska smjesa je zatim podijeljena između etera (50 cm3) i zasićene otopine amonijevog klorida (25 cm3), pa su slojevi odvojeni. Vodena faza je ekstrahirana sa dietil eterom (2 x 10 cm3) i kombinirani organski ekstrakti su isprani sa slanom otopinom, sušeni (Na2SO4) i isparavani. Sirovi materijal je pročišćen fleš-kromatografijom na silikagelu, uz eluiranje sa 3-10% etil acetat/60-80°C petrol eterom, da bi dali blijedo žutu gumu. Doprinos:0.77 g, 45%. To a solution of methyllithium (1.4 M in ether, 14.5 cm3, 12.4 mmol) in dry THF (20 cm3) at -78°C under a nitrogen atmosphere, in a flame-dried flask, a solution of 9b,10- was added dropwise over the course of 1 hour. of dihydro-9b-methyl-8-isopropylindeno[1,2-b]indole (1.62 g, 6.20 mmol) in dry THF (30 cm3). After the addition, the mixture was stirred for another half hour at -78°C. A saturated solution of ammonium chloride (2 cm3) was then added, and the mixture was allowed to warm to room temperature. The reaction mixture was then partitioned between ether (50 cm 3 ) and saturated ammonium chloride solution (25 cm 3 ), and the layers were separated. The aqueous phase was extracted with diethyl ether (2 x 10 cm 3 ) and the combined organic extracts were washed with brine, dried (Na 2 SO 4 ) and evaporated. The crude material was purified by flash chromatography on silica gel, eluting with 3-10% ethyl acetate/60-80°C petroleum ether, to give a pale yellow gum. Contribution: 0.77 g, 45%.

1H NMR (CDCl3), δ : 7.1-7.3 (4H, m), 6.98 (1H, d, J=1.8Hz), 6.82 (1H, dd, J=1.8Hz and 7.9Hz), 6.47 (1H, d, J=7.9Hz), 3.36 (1H, d, J=15.9Hz), 3.06 (1H, d, J=15.9Hz), 2.78 (1H, sept., J=6.8Hz), 1.45 (3H, s), 1.34 (3H, s) 1.18 (6H, dd, J=1.3Hz and 6.9Hz). 1H NMR (CDCl3), δ : 7.1-7.3 (4H, m), 6.98 (1H, d, J=1.8Hz), 6.82 (1H, dd, J=1.8Hz and 7.9Hz), 6.47 (1H, d, J=7.9Hz), 3.36 (1H, d, J=15.9Hz), 3.06 (1H, d, J=15.9Hz), 2.78 (1H, sept., J=6.8Hz), 1.45 (3H, s), 1.34 (3H, s) 1.18 (6H, dd, J=1.3Hz and 6.9Hz).

Primjer 31 Example 31

cis-5-Acetil-4b,5,9b,10-tetrahidro-4b,8,9b-trimetilindeno[1,2-b]indol cis-5-Acetyl-4b,5,9b,10-tetrahydro-4b,8,9b-trimethylindeno[1,2-b]indole

4b,5,9b,10-tetrahidro-4b,8,9b-trimetilindeno[1,2-b]indol (0.25 g, 1.00 mmol) je otopljen u anhidridu octene kiseline (1 cm3) i miješan je 16 sati na sobnoj temperaturi. Reakcijska smjesa je prosuta u zasićenu otopinu natrijevog bikarbonata (25 cm3) i miješana je pola sata. Smjesa je ekstrahirana sa dietil eterom (3 x 10 cm3) i kombinirani organski ekstrakti su isprani slanom otopinom, sušeni (Na2 SO4) i isparavani. Sirovi materijal je pročišćen fleš-kromatografijom na silikagelu, uz eluiranje sa 4% etil acetat/60-80°C petrol eterom, da bi se dobila bijelo žuta guma. Doprinos: 0.15 g, 53%. 4b,5,9b,10-tetrahydro-4b,8,9b-trimethylindeno[1,2-b]indole (0.25 g, 1.00 mmol) was dissolved in acetic anhydride (1 cm3) and stirred for 16 hours at room temperature . The reaction mixture was poured into saturated sodium bicarbonate solution (25 cm3) and stirred for half an hour. The mixture was extracted with diethyl ether (3 x 10 cm 3 ) and the combined organic extracts were washed with brine, dried (Na 2 SO 4 ) and evaporated. The crude material was purified by flash chromatography on silica gel, eluting with 4% ethyl acetate/60-80°C petroleum ether, to give a white-yellow gum. Contribution: 0.15 g, 53%.

1H NMR (CDCl3), δ : 7.84 (1H, s), 6.90-7.23 (6H, m), 3.26 (1H, d, J=15.9Hz), 2.96 (1H, d, J=15.9Hz), 2.40 (3H, s), 2.31 (3H, s), 1.77 (3H, s), 1.32 (3H, s). 1H NMR (CDCl3), δ : 7.84 (1H, s), 6.90-7.23 (6H, m), 3.26 (1H, d, J=15.9Hz), 2.96 (1H, d, J=15.9Hz), 2.40 ( 3H, s), 2.31 (3H, s), 1.77 (3H, s), 1.32 (3H, s).

Primjer 32 Example 32

cis-5-Acetil-4b,5,9b,10-tetrahidro-4b,8,9b-dimetil-8-izopropilindeno[1,2-b]indol cis-5-Acetyl-4b,5,9b,10-tetrahydro-4b,8,9b-dimethyl-8-isopropylindeno[1,2-b]indole

4b,5,9b,10-Tetrahidro-4b,8,9b-dimetil-8-izopropilindeno[1,2-b]indol (0.24 g, 0.87 mmol) je otopljen u anhidridu octene kiseline (1 cm3) i miješan na sobnoj temperaturi tokom 16 sati. Reakcijska smjesa je prosuta u zasićenu otopinu natrijevog bikarbonata (25 cm3) i miješana je pola sata. Smjesa je ekstrahiranas eterom (3 x 25 cm3). Kombinirani organski ekstrakti su isprani sa slanom otopinom, sušeni (Na2 SO4) i isparavani. Sirovi materijal je pročišćen fleš-kromatografijom na silikagelu uz eluiranje sa 4% etil/acetat/60-80°C petrol eterom, pa je dao blijedo žutu boju. Doprinos: 0.25 g, 89%. 4b,5,9b,10-Tetrahydro-4b,8,9b-dimethyl-8-isopropylindeno[1,2-b]indole (0.24 g, 0.87 mmol) was dissolved in acetic anhydride (1 cm3) and stirred at room temperature. temperature for 16 hours. The reaction mixture was poured into saturated sodium bicarbonate solution (25 cm3) and stirred for half an hour. The mixture was extracted with ether (3 x 25 cm3). The combined organic extracts were washed with brine, dried (Na2SO4) and evaporated. The crude material was purified by flash chromatography on silica gel eluting with 4% ethyl/acetate/60-80°C petroleum ether, giving a pale yellow color. Contribution: 0.25 g, 89%.

1H NMR (CDCl3), δ : 7.84 (1H, s), 6.90-7.24 (6h, m), 3.27 (1H, d, J=15.9Hz), 2.97 (1H, d, J=15.9Hz), 2.88 (1H, sept., J=6.8Hz), 2.40 (3H, s), 1.77 (3H, s), 1.33 (3H, s), 1.23 (6H, dd, J=0.73Hz and 6.8Hz). 1H NMR (CDCl3), δ : 7.84 (1H, s), 6.90-7.24 (6h, m), 3.27 (1H, d, J=15.9Hz), 2.97 (1H, d, J=15.9Hz), 2.88 ( 1H, sept., J=6.8Hz), 2.40 (3H, s), 1.77 (3H, s), 1.33 (3H, s), 1.23 (6H, dd, J=0.73Hz and 6.8Hz).

Primjer 33 Example 33

cis-4b,5,9b,10-Tetrahidro-5-etilindeno[1,2-b]indol cis-4b,5,9b,10-Tetrahydro-5-ethylindeno[1,2-b]indole

5,10-Dihidroindeno[1,2-b]indol (60.0 g, 0.29 M) jako je miješan u glacijalnoj octenoj kiselini (1000 cm3), te mu je postepeno, tokom 40 minuta, dodavan natrijev cijanoborohidrid (79 g, 1.25 M). Nakon 3 sata miješanja reakcijska smjesa prosuta je preko leda/vode (2000 cm3) i želatinaste krute supstancije koja se formurala, te je miješana sa smjesom etil acetata (75 cm3) i vode (100 cm3). Bezbojna kruta supstancija koja zaostaje predstavljala je, kako se pokazalo, neizreagirani početni materijal (19.0 g). Originalni filtrat je ekstrahiran s etil acetatom (2 x 75 cm3), a kombinirani organski ekstrakti su sušeni i isparavani. Ostatak je zatim djelomično otopljen u smjesi 60-80°C petrol etera (20 cm3) i etil acetata (40 cm3). Rezidualna kruta supstancija je uklonjena i pokazalo se da predstavlja neizreagirani početni materijal (2.5 g). Filtrat je ekstrahiran sa 2M klorovodikovom kiselinom (8 x 25 cm3), a kombinirani kiseli ekstrakti su isprani s etil acetatom (2x 15 cm3), prije alkaliziranja s 0.89 g amonijaka. Ulje koje se odvojilo je ekstrahirano s etil acetatom (6 x 25 cm3), a kombinirani organski slojevi su zatim sušeni i ispraravani da bi dali naslovni spoj kao bezbojno ulje. Doprinos: 34 g, 75%. 5,10-Dihydroindeno[1,2-b]indole (60.0 g, 0.29 M) was thoroughly stirred in glacial acetic acid (1000 cm3), and sodium cyanoborohydride (79 g, 1.25 M) was gradually added over 40 minutes. ). After stirring for 3 hours, the reaction mixture was poured over ice/water (2000 cm3) and the gelatinous solid that had formed, and mixed with a mixture of ethyl acetate (75 cm3) and water (100 cm3). The colorless solid that remained was, as it turned out, the unreacted starting material (19.0 g). The original filtrate was extracted with ethyl acetate (2 x 75 cm3), and the combined organic extracts were dried and evaporated. The residue was then partially dissolved in a mixture of 60-80°C petroleum ether (20 cm3) and ethyl acetate (40 cm3). The residual solid was removed and was found to represent unreacted starting material (2.5 g). The filtrate was extracted with 2M hydrochloric acid (8 x 25 cm3), and the combined acid extracts were washed with ethyl acetate (2 x 15 cm3), before basification with 0.89 g of ammonia. The oil that separated was extracted with ethyl acetate (6 x 25 cm 3 ) and the combined organic layers were then dried and washed to give the title compound as a colorless oil. Contribution: 34 g, 75%.

1H NMR (CDCl3), δ : 1.20 (3H, t, J=7.0Hz), 3.05 (1H, dd, J=16.5Hz and 5.0Hz), 3.38 (2H, q, J=7.0Hz), 3.40 (1H, dd, J=16.5 and 9.0Hz), 4.12 (1H, ddd, J=9.0, 5.0 and 5.0Hz), 5.11 (1H, d, J=9.0Hz), 6.33 (1H, d, J=7.0Hz), 6.57 (1H, dt, J=7.5 and 1.0Hz), 7.02 (1H, t; J=8.0Hz), 7.14-7.20 (3H, m), 7.34-7.40 (1H, m). 1H NMR (CDCl3), δ : 1.20 (3H, t, J=7.0Hz), 3.05 (1H, dd, J=16.5Hz and 5.0Hz), 3.38 (2H, q, J=7.0Hz), 3.40 (1H , dd, J=16.5 and 9.0Hz), 4.12 (1H, ddd, J=9.0, 5.0 and 5.0Hz), 5.11 (1H, d, J=9.0Hz), 6.33 (1H, d, J=7.0Hz) , 6.57 (1H, dt, J=7.5 and 1.0Hz), 7.02 (1H, t; J=8.0Hz), 7.14-7.20 (3H, m), 7.34-7.40 (1H, m).

Primjer 34 Example 34

cis-4b,5,9b,10-Tetrahidro-2-(N,N-dietilamino)indeno[1,2-b]indol cis-4b,5,9b,10-Tetrahydro-2-(N,N-diethylamino)indeno[1,2-b]indole

5,10-Dihidro-2-(N,N-dietilamino)indeno[1,2-b]indol (180 mg, 0.65 mM) otopljen je u triflorooctenoj kiselini (3 cm3) koja sadrži trietilsilan (0.5 cm3), pa je otopina miješana na sobnoj temperaturi tokom 3 sata. Otopina je zatim tretirana s vodom (15 cm3) i 0.89 amonijakom (5 cm3), te je miješana još pola sata. Smjesa je ekstrahirana sa diklormetanom (3 x 5 cm3), pa su kombinirani ekstrakti filtrirani kroz papir za odvajanje faza i isparavani da bi dali blijedo žuto ulje (280 mg). Ulje je podvrgnuto kromatografiji na koloni (silikagel; 7.5% EtOAc u 60-80°C petrol eteru) da bi dalo naslovni spoj kao bezbojne iglice. Doprinos: 65 mg, 35%. T.t. 116-118°C. Ovaj proizvod je prekristaliziran iz dietil etera/60-80°C petrol etera, u obliku dugih bezbojnih iglica. T.t. 118°C; 5,10-Dihydro-2-(N,N-diethylamino)indeno[1,2-b]indole (180 mg, 0.65 mM) was dissolved in trifluoroacetic acid (3 cm3) containing triethylsilane (0.5 cm3), so the solution was stirred at room temperature for 3 hours. The solution was then treated with water (15 cm3) and 0.89 ammonia (5 cm3) and stirred for another half hour. The mixture was extracted with dichloromethane (3 x 5 cm 3 ), and the combined extracts were filtered through phase separation paper and evaporated to give a pale yellow oil (280 mg). The oil was subjected to column chromatography (silica gel; 7.5% EtOAc in 60-80°C petroleum ether) to give the title compound as colorless needles. Contribution: 65 mg, 35%. T.t. 116-118°C. This product was recrystallized from diethyl ether/60-80°C petroleum ether, in the form of long colorless needles. T.t. 118°C;

1H NMR (CDCl3), δ : 1.08 (6H, t, J=7.0Hz), 3.10 (1H, dd, J=16.0 and 2.0Hz), 3.25 (4H, q, J=7.0Hz), 3.42 (1H, dd, J=16.0 and 8.5Hz), 3.55 (1H, br. s), 4.10 (1H, ddd, J=8.5, and 2.0Hz), 5.13 (1H, d, J=8.5Hz), 6.46 (1H, d, J=2.0Hz), 6.50-6.60 (2H, m), 6.70 (1H, ddd, J=7.0, 7.0 and 1.0Hz), 6.95 (1H, ddd, J=7.0, 7.0 and 1.0Hz), 7.06-7.13 (2H, m). 1H NMR (CDCl3), δ : 1.08 (6H, t, J=7.0Hz), 3.10 (1H, dd, J=16.0 and 2.0Hz), 3.25 (4H, q, J=7.0Hz), 3.42 (1H, dd, J=16.0 and 8.5Hz), 3.55 (1H, no. s), 4.10 (1H, ddd, J=8.5, and 2.0Hz), 5.13 (1H, d, J=8.5Hz), 6.46 (1H, d, J=2.0Hz), 6.50-6.60 (2H, m), 6.70 (1H, ddd, J=7.0, 7.0 and 1.0Hz), 6.95 (1H, ddd, J=7.0, 7.0 and 1.0Hz), 7.06 -7.13 (2H, m).

Primjer 35 Example 35

cis-(E)-i (Z)-4b,5,9b,10-Tetrahidro-5-acetil-8-(N,N-dietilamino)indeno[1,2-b]indol cis-(E)-i (Z)-4b,5,9b,10-Tetrahydro-5-acetyl-8-(N,N-diethylamino)indeno[1,2-b]indole

(E)- i (Z)-4b,5,9b,10-Tetrahidro-5-acetil-8-amino-indeno[1,2-b]indol (1.0 g), natrijev karbonat (1 g) i etil jodid (2.0 cm3) zajedno su zagrijavani na temperaturi refluksa u smjesi THF (80 cm3) i vode (15 cm3), tokom 24 sata uz miješanje. Dodano je još etil jodida (0.5 cm3), te je miješanje nastavljeno na još 3 sata. Otapalo je ispareno, a ostatku je dodan diklorometan. Krute supstancije su uklonjene filtriranjem, a zatim su dobro isprane dietil eterom. Filtrat i tekućina od ispiranja su kombinirane i opseg im je smanjen na oko 15 cm3. Nakon hlađenja naslovni se spoj odvojio kao blijedo žuta prizma. Doprinos: 0.75 g, 62%. T.t. 176-178°C; (E)- and (Z)-4b,5,9b,10-Tetrahydro-5-acetyl-8-amino-indeno[1,2-b]indole (1.0 g), sodium carbonate (1 g) and ethyl iodide (2.0 cm3) were heated together at reflux temperature in a mixture of THF (80 cm3) and water (15 cm3) for 24 hours with stirring. More ethyl iodide (0.5 cm3) was added, and stirring was continued for another 3 hours. The solvent was evaporated and dichloromethane was added to the residue. The solids were removed by filtration and then washed well with diethyl ether. The filtrate and washing liquid were combined and their volume was reduced to about 15 cm3. After cooling, the title compound separated as a pale yellow prism. Contribution: 0.75 g, 62%. T.t. 176-178°C;

1H NMR (CDCl3) δ : .110 (6H, t, J=7.0Hz), 1.13 (6H, t, J=7.0Hz), 2.43 (3H, s), 2.45 (3H, s), 3.21 (1H, d, J=16Hz), 3.29 (10Hz), m), 4.06 (1H, dd, J0J=8Hz), 4.16 (1H, dd, J=J=7.5Hz), 5.56 (1H, d, J=2Hz), 5.72 (1H, d, J=7.5Hz), 6.27 (1H, d, J=8Hz), 6.47 (2H, ddd, J=7.5, J=2Hz), 6.63 (1H, d, J=2Hz), 6.90 (1H, d, J=9Hz), 7.15-7.23 (6H, m), 7.41 (1H, m), 7.60 (1H, m), 7.89 (1H, d, J=9Hz). 1H NMR (CDCl3) δ : .110 (6H, t, J=7.0Hz), 1.13 (6H, t, J=7.0Hz), 2.43 (3H, s), 2.45 (3H, s), 3.21 (1H, d, J=16Hz), 3.29 (10Hz), m), 4.06 (1H, dd, J0J=8Hz), 4.16 (1H, dd, J=J=7.5Hz), 5.56 (1H, d, J=2Hz) , 5.72 (1H, d, J=7.5Hz), 6.27 (1H, d, J=8Hz), 6.47 (2H, ddd, J=7.5, J=2Hz), 6.63 (1H, d, J=2Hz), 6.90 (1H, d, J=9Hz), 7.15-7.23 (6H, m), 7.41 (1H, m), 7.60 (1H, m), 7.89 (1H, d, J=9Hz).

Primjer 36 Example 36

cis-4b,5,9b,10-Tetrahidro-5-acetil-8-(N,N-dietilamino)indeno[1,2-b]indol cis-4b,5,9b,10-Tetrahydro-5-acetyl-8-(N,N-diethylamino)indeno[1,2-b]indole

cis-(E)- i (Z)-4b,5,9b,10-Tetrahidor-5-acetil-8-(N,N-dietilamino)-indeno[1,2-b]indoli (0.32 g, 1mM) u suhom THF (60 cm3) su tretirani litij aluminij hidridom (0.38 g, 10 mM) postepeno, tokom 30 minuta. Reakcijska smjesa je zatim zagrijavana na refluksu tokom 3 sata i višak reagensa je uništen dodatkom 30% natrij amonijak tarkarata. Organsko otapalo je zatim dekantiran i ostatak je ekstrahiran na THF (3 x 10 cm3). Otapalo i tekućina su kombinirani, sušeni i isparavani, da bi dali ulje koje je aposrbirano na silikagel (1 g) i dodano na vrh kolone silikagela (5 g) prije eluiranja sa 10% etil acetatom u 60-80°C petrol eteru. Boja kolone je postala tamno plava, ali je naslovni spoj eluiran kao bezbojno ulje. Doprinos: 0.2 g, 65%. Spoj je nestabilan na zraku - prvo postaje plavo, a kasnije tamno crveno. cis-(E)- and (Z)-4b,5,9b,10-Tetrahydro-5-acetyl-8-(N,N-diethylamino)-indeno[1,2-b]indoles (0.32 g, 1mM) in dry THF (60 cm3) were treated with lithium aluminum hydride (0.38 g, 10 mM) gradually over 30 minutes. The reaction mixture was then heated at reflux for 3 hours and the excess reagent was destroyed by the addition of 30% sodium ammonia tartrate. The organic solvent was then decanted and the residue was extracted into THF (3 x 10 cm3). The solvent and liquid were combined, dried and evaporated to give an oil which was adsorbed onto silica gel (1 g) and added to the top of a silica gel column (5 g) before eluting with 10% ethyl acetate in 60-80°C petroleum ether. The color of the column turned dark blue, but the title compound eluted as a colorless oil. Contribution: 0.2 g, 65%. The compound is unstable in air - first it turns blue and later dark red.

1H NMR (CDCl3) δ : 1.09 (6H, t, J=7.0Hz), 1.27 (3H, t, J=7.0Hz), 3.1-3-3(5H, m), 3.3-3.5 (3H, m), 4.18 (1H, br. s), 5.07 (1H, br. s), 6.40 (1H, d, J=7.0Hz), 6.57 (1H, d, J=7.0Hz), 6.74 (1H, s), 7.22 (3H, s), 7.43 (1H, m). 1H NMR (CDCl3) δ : 1.09 (6H, t, J=7.0Hz), 1.27 (3H, t, J=7.0Hz), 3.1-3-3(5H, m), 3.3-3.5 (3H, m) , 4.18 (1H, no. s), 5.07 (1H, no. s), 6.40 (1H, d, J=7.0Hz), 6.57 (1H, d, J=7.0Hz), 6.74 (1H, s), 7.22 (3H, s), 7.43 (1H, m).

Primjer 37 Example 37

Otopina 5,10-dihidro-8-terc-butilindeno[1,2-b]indola (0.57 g, 2.2 mM) u trifluorooctenoj kiselini (5 cm3) brzo je miješana, te mu je dodan trietilsilan (0.7 cm3), 2 ekvivalenta). Reakcijska smjesa je miješana preko noći, prosuta u vodu (10 cm3), i neutralizirana dodatkom natrijevog hidroksida. Proizvod je ekstrahiran sa dietil eterom (2 x 5 cm3), pa su kombinirani ekstrakti isprani vodom, sušeni (Na2SO4) i isparavani da bi dali roza krutu supstanciju. Ova supstancija je isprana petrol eterom (60-80°C) i zatim kristaliziran iz petrol etera da bi dala naslovni spoj kao bezbojnu krutu supstanciju. Doprinos: 0.47 g, 81%. T.t. 103-105°C. A solution of 5,10-dihydro-8-tert-butylindeno[1,2-b]indole (0.57 g, 2.2 mM) in trifluoroacetic acid (5 cm3) was stirred rapidly, and triethylsilane (0.7 cm3), 2 equiv. ). The reaction mixture was stirred overnight, poured into water (10 cm3), and neutralized by the addition of sodium hydroxide. The product was extracted with diethyl ether (2 x 5 cm3), and the combined extracts were washed with water, dried (Na2SO4) and evaporated to give a pink solid. This substance was washed with petroleum ether (60-80°C) and then crystallized from petroleum ether to give the title compound as a colorless solid. Contribution: 0.47 g, 81%. T.t. 103-105°C.

1H NMR (CDCl3) δ : 7.4-6.9 (6H, m), 6.58 (1H, d, J=8Hz), 5.25 (1H, d, J=8.5Hz), 4.15 (2H, br. m), 3.5 (1H, dd, J=16.0 and 9Hz), 3.2 (1H, d, J=16Hz), 1.2 (9H, s). 1H NMR (CDCl3) δ : 7.4-6.9 (6H, m), 6.58 (1H, d, J=8Hz), 5.25 (1H, d, J=8.5Hz), 4.15 (2H, no. m), 3.5 ( 1H, d, J=16.0 and 9Hz), 3.2 (1H, d, J=16Hz), 1.2 (9H, s).

Primjer 38 Example 38

cis-4b,5,9b,10-Tetrahidro-5-metil-8-terc-butilindeno[1,2-b]indol cis-4b,5,9b,10-Tetrahydro-5-methyl-8-tert-butylindeno[1,2-b]indole

Balon sušen na plamenu napunjen je sa 4b,5,9b,10-tetrahidro-8-terc-butilindeno[1,2-b]indolom (309 mg, 1.17 mM) i THF (2.5 cm3). Otopina je ohlađena do -78°C i u kapima je dodana otopina n-butillitija (0.75 cm3), 1.6 M otopine u heksanu, 1.1 ekvivalent). Reakcijska smjesa miješana je na -78°C jedan sat, pa je dodan jodometan (0.1 cm3), 1.3 ekvivalenta). Nakon što je rekacijska smjesa ostavljena da se polako zagrije do sobne temperature, dodana je zasićena otopina amonijak klorida, pa je organski materijal ekstrahiran sa dietil eterom. Organska faza je isprana sa slanom otopinom, te je sušena. Isparavanje otapala dalo je svijetlo smeđe ulje koje se stajanjem ukrutilo u krutu supstanciju boje mesa. Doprinos: 311 mg, 96%. M.p. 74°C; A flame-dried flask was charged with 4b,5,9b,10-tetrahydro-8-tert-butylindeno[1,2-b]indole (309 mg, 1.17 mM) and THF (2.5 cm3). The solution was cooled to -78°C and a solution of n-butyllithium (0.75 cm3), 1.6 M solution in hexane, 1.1 equivalent) was added dropwise. The reaction mixture was stirred at -78°C for one hour, then iodomethane (0.1 cm3, 1.3 equivalents) was added. After the reaction mixture was allowed to slowly warm to room temperature, a saturated solution of ammonia chloride was added, and the organic material was extracted with diethyl ether. The organic phase was washed with saline and dried. Evaporation of the solvent gave a light brown oil which solidified on standing to a flesh-colored solid. Contribution: 311 mg, 96%. MP 74°C;

1H NMR (CDCl3) δ : 7.5-7.0 (6H, m), 6.32 (1H, d, J=8.3 Hz), 4.91 (1H, d, J=8.8Hz), 4.16 (1H, ddd, J=9.0, 8.8 and 5.3Hz), 3.44 (1H, dd, J=16.3 and 9.1Hz), 3.10 (1H, dd, J=16.3 and 5.3Hz), 2.95 (3H, s), 1.29 (9H, s). 1H NMR (CDCl3) δ : 7.5-7.0 (6H, m), 6.32 (1H, d, J=8.3 Hz), 4.91 (1H, d, J=8.8Hz), 4.16 (1H, ddd, J=9.0, 8.8 and 5.3Hz), 3.44 (1H, dd, J=16.3 and 9.1Hz), 3.10 (1H, dd, J=16.3 and 5.3Hz), 2.95 (3H, s), 1.29 (9H, s).

Primjer 39 Example 39

cis-4b,5,9b,10-Tetrahidro-4b-metil-8-terc-butilindeno[1,2-b]indol cis-4b,5,9b,10-Tetrahydro-4b-methyl-8-tert-butylindeno[1,2-b]indole

Balon sušen na plamenu propuhan je sa dušikom i napunjen sa 4b,5,9b,10-tetrahidro-8-terc-butilindeno[1,2-b]indolom (240 mg, 0.91 mM) i svježe destiliranim THF (3 cm3). Otopina je ohlađena do -78°C i u kapima je dodan n-butillitij (0.60 cm3 1.6 M otopine u heksanu, 1.1 ekvivalent). Blijedo žuta otopina ostavljena je da se zagrije do sobne temperature i kroz otopinu je propuhavan suhi plinoviti ugljen dioksid, sve dok otopina nije postala praktički bezbojna. Otapalo je pažljivo uklonjeno pod smanjenim tlakom i ponovno je uspostavljena atmosfera dušika. Bezbojni ostatak je ponovno otopljen u suhom THF (3 cm3), ootpina je ohlađena na -78°C tokom 2 sata i zatim je tretirana s jodometanom (0.06 cm3), 1.1 ekvivalent). Nakon što se smjesa zagrijala do sobne temperature, otapala su uklonjena i dodana je 2M otopina Hcl (20 cm3). Nakon prestanka izdvajanja plina (oko 20 minuta), otopina je neutralizirana s krutim natrijevim karbonatom. Organski materijal je ekstrahiran sa diklorometanom (3 x 5 cm3) pa su kombinirani organski ekstrakti isprani slanom otopinom i sušeni (Na2SO4). Nakon uklanjanja otapala, čvrsti proizvod koji zaostaje pročišćen je fleš-kromatografijom Rf = 0.4 (10% EtOAc/60-80°C petrol eter) uz eluiranje sa 10% etil acetat/60-80° petrol eterom. Dobiveno je blijedo žuto ulje koje se krutilo na -20°C kao voskasta kruta supstancija. Doprinos: 0.86 mg, 34%. T.t. 82.84°C. A flame-dried flask was purged with nitrogen and charged with 4b,5,9b,10-tetrahydro-8-tert-butylindeno[1,2-b]indole (240 mg, 0.91 mM) and freshly distilled THF (3 cm3). The solution was cooled to -78°C and n-butyllithium was added dropwise (0.60 cm3 of a 1.6 M solution in hexane, 1.1 equivalent). The pale yellow solution was allowed to warm to room temperature and dry carbon dioxide gas was bubbled through the solution until the solution became practically colorless. The solvent was carefully removed under reduced pressure and a nitrogen atmosphere was reestablished. The colorless residue was redissolved in dry THF (3 cm3), the solution was cooled to -78°C for 2 hours and then treated with iodomethane (0.06 cm3, 1.1 equiv). After the mixture warmed to room temperature, the solvents were removed and a 2M HCl solution (20 cm3) was added. After gas evolution stopped (about 20 minutes), the solution was neutralized with solid sodium carbonate. The organic material was extracted with dichloromethane (3 x 5 cm3) and the combined organic extracts were washed with brine and dried (Na2SO4). After removal of the solvent, the remaining solid product was purified by flash chromatography Rf = 0.4 (10% EtOAc/60-80°C petroleum ether) eluting with 10% ethyl acetate/60-80° petroleum ether. A pale yellow oil was obtained which solidified at -20°C as a waxy solid. Contribution: 0.86 mg, 34%. T.t. 82.84°C.

1H NMR (CDCl3) δ : 7.4-7.0 (6H, m), 6.49 (1H, d, J=9.0Hz), 4.15 (1H, br. m), 3.71 (1H, br. m), 3.51 (1H, dd, J=16.0Hz), 3.17 (1H, dd, J=16.0 and 5Hz), 1.61 (3H, s), 1.27 (9H, s). 1H NMR (CDCl3) δ : 7.4-7.0 (6H, m), 6.49 (1H, d, J=9.0Hz), 4.15 (1H, no. m), 3.71 (1H, no. m), 3.51 (1H, dd, J=16.0Hz), 3.17 (1H, dd, J=16.0 and 5Hz), 1.61 (3H, s), 1.27 (9H, s).

Primjer 40 Example 40

cis-4b,5,9b,10-Tetrahidro-8-floroindeno[1,2-b]indol cis-4b,5,9b,10-Tetrahydro-8-fluoroindeno[1,2-b]indole

Otopina 5,10-dihidro-8-floroindeno[1,2-b]indola (0.8 g, 3.6 mM) u triflorooctenoj kiselini (5, cm3) brzo je miješana, te mu je dodan trietilsilan (0.86 cm3, 1.5 ekvivalent). Reakcijska smjesa je miješana 4 sata i višak triflorooctene kiseline je stavljen pod vakuum. Krutoj supstanciji dodana je voda (10 cm3), pa je suspenzija neutralizirana dodatkom natrijevog hidroksida. Proizvod je ekstrahiran sa dietil eterom koji je zatim ispran s vodom, sušen i isparavan da bi dao bijeličastu krutu supstanciju. Ova supstancija je kristalizirana iz etil acetat/petrol etera (60-80°C) da bi se dobio naslovni spoj. Doprinos: 0.53 g, 82%. T.t. 92-94°C. A solution of 5,10-dihydro-8-fluoroindeno[1,2-b]indole (0.8 g, 3.6 mM) in trifluoroacetic acid (5, cm3) was stirred rapidly, and triethylsilane (0.86 cm3, 1.5 equiv) was added. The reaction mixture was stirred for 4 hours and excess trifluoroacetic acid was placed under vacuum. Water (10 cm3) was added to the solid substance, and the suspension was neutralized by adding sodium hydroxide. The product was extracted with diethyl ether which was then washed with water, dried and evaporated to give an off-white solid. This substance was crystallized from ethyl acetate/petroleum ether (60-80°C) to give the title compound. Contribution: 0.53 g, 82%. T.t. 92-94°C.

1H NMR (CDCl3) δ : 7.34 (1H, m), 7.8-7.2 (3H, m), 6.87 (1H, m), 6.69 (1H, m), 6.52 (1H, dd, J=8.4 and 4.4Hz), 5.27 (1H, d, J=8.8Hz), 4.16 (1H, ddm, J=8.8 and 8.3Hz), 4.1 (1H, br. s), 3.51 (1H, dd, J=16.5 and 8.3Hz), 3.18 (1H, dd, J=16.5 and 2.0Hz). 1H NMR (CDCl3) δ : 7.34 (1H, m), 7.8-7.2 (3H, m), 6.87 (1H, m), 6.69 (1H, m), 6.52 (1H, dd, J=8.4 and 4.4Hz) , 5.27 (1H, d, J=8.8Hz), 4.16 (1H, ddm, J=8.8 and 8.3Hz), 4.1 (1H, no. s), 3.51 (1H, dd, J=16.5 and 8.3Hz), 3.18 (1H, dd, J=16.5 and 2.0Hz).

Primjer 41 Example 41

cis-4b,5,9b,10-Tetrahidro-3,7-dinitroindeno[1,2-b]indol cis-4b,5,9b,10-Tetrahydro-3,7-dinitroindeno[1,2-b]indole

Otopina cis-4b,5,9b,10-tetrahidroindeno[1,2-b]indola (1.0 g, 4.8 mM) u koncentriranoj sumpornoj kiselini (20 cm3) jako je miješana tokom 45 minuta i zatim je ohlađena na 0°C i tretirana kalijevim nitratom (0.7 g, 6.9 mM) koji je dodavan u malim količinama tokom 15 minuta. Otopina boje višnje miješana je na 0°C još 15 minuta, a zatim je prelivena preko leda. Formirana je žuta kruta supstancija prikupljena je filtriranjem i isprana prvo s vodom a zatim s vrućom otopinom 25% etanola u vodi (30 cm3). Filtrat nakon posljednjeg ispiranja ostavljen je da se ohladi, pa je naslovni spoj izoliran u obliku pelete žarko žute boje. Doprinos: 0.45 g, 31%. T.t. 174-176°C. A solution of cis-4b,5,9b,10-tetrahydroindeno[1,2-b]indole (1.0 g, 4.8 mM) in concentrated sulfuric acid (20 cm3) was stirred vigorously for 45 min and then cooled to 0°C and treated with potassium nitrate (0.7 g, 6.9 mM) which was added in small amounts over 15 minutes. The cherry colored solution was stirred at 0°C for another 15 minutes and then poured over ice. A yellow solid formed was collected by filtration and washed first with water and then with a hot solution of 25% ethanol in water (30 cm3). The filtrate after the last wash was allowed to cool, and the title compound was isolated as a bright yellow pellet. Contribution: 0.45 g, 31%. T.t. 174-176°C.

1H NMR (CDCl3) δ : 3.30 (1H, dd, j=17.5 and 1.0Hz), 3.65 (1H, dd, J=17.5 and 8.5Hz), 4.20 (1H, br. s), 4.33 (1H, t, J=8.5Hz), 5.41 (1H, d, J=8.5Hz), 7.22 (1H, dd, J=8.0 and 1.0Hz), 7.28 (1H, d, J=2.0Hz), 7.38 (1H, d, J=8.5Hz), 7.50 (1H, dd, J=8.0 and 2.0Hz), 8.17 (1H, dd, J=8.5 and 2.0Hz), 8.40 (1H, d, J=2.0Hz). 1H NMR (CDCl3) δ : 3.30 (1H, dd, j=17.5 and 1.0Hz), 3.65 (1H, dd, J=17.5 and 8.5Hz), 4.20 (1H, no. s), 4.33 (1H, t, J=8.5Hz), 5.41 (1H, d, J=8.5Hz), 7.22 (1H, dd, J=8.0 and 1.0Hz), 7.28 (1H, d, J=2.0Hz), 7.38 (1H, d, J=8.5Hz), 7.50 (1H, dd, J=8.0 and 2.0Hz), 8.17 (1H, dd, J=8.5 and 2.0Hz), 8.40 (1H, d, J=2.0Hz).

Primjer 42 Example 42

cis-4b,5,9b,10-Tetrahidro-5-acetil-3,7-dinitroindeno[1,2-b]indol cis-4b,5,9b,10-Tetrahydro-5-acetyl-3,7-dinitroindeno[1,2-b]indole

cis-4b,5,9b,10-Tetrahidro-3,7-dinitroindeno[1,2-b]indol (0.40 g, 1.35 mM) i anhidrid octene kiseline (1.5 cm3) zagrijavani su na 90°C 1 sat, ohlađeni i prosuti u vodu (7 cm3) i led, te je smjesa miješana 30 minuta. Bezbojna kruta supstancija koja se staložila prikupljena je i otopljena u vrućem etanolu. Nakon filtriranja na vruće, naslovni spoj se iz hladnog filtrata izdvojio u obliku prizmi. Doprinos: 42 g, 92%. T.t. 164-166°C. cis-4b,5,9b,10-Tetrahydro-3,7-dinitroindeno[1,2-b]indole (0.40 g, 1.35 mM) and acetic anhydride (1.5 cm3) were heated at 90°C for 1 hour, cooled and poured into water (7 cm3) and ice, and the mixture was stirred for 30 minutes. The colorless solid that settled was collected and dissolved in hot ethanol. After hot filtration, the title compound separated from the cold filtrate in the form of prisms. Contribution: 42 g, 92%. T.t. 164-166°C.

Primjer 43 Example 43

cis-(E) i (Z)-4b,5,9b,10-Tetrahidro-5-acetil-3,7d-dinitroindeno[1,2-b]indol cis-(E) and (Z)-4b,5,9b,10-Tetrahydro-5-acetyl-3,7d-dinitroindeno[1,2-b]indole

cis-4b,5,9b,10-Tetrahidro-5-acetil-3,7d-dinitroindeno[1,2-b]indol (0.4 g, 1.2 mM) miješan je u otopini glacijalne octene kiseline (30 cm3) i vode (5 cm3). Ovoj smjesi je dodan titan triklorid (3 cm3 30% otopine u 24% vodenoj klorovodikovoj kiselini) tokom 5 minuta. Nakon još 2 sata reakcijska smjesa je postala bezbojna i dodano je još (0.5 cm3) titan trikloridnog reagensa. Neizreagirani početni materijal je odfiltriran (0.13 g) i filtrat je preliven preko lomljivog leda. pH otopine koji je tako dobiven namješteno je na 6 (15 cm3, 0.89 amonijak) i proizvod je ekstrahiran s etil acetatom (8 x 50 cm3). Ova ekstrakcija je bila vrlo spora, jer se gradi emulzija, pa je trajala 3 dana. Ekstrakti su kombinirani i isparavani, da bi se dobila zelenkasta kruta supstancija koja je triturirana sa dietil eterom da bi dala bezbojne mikro prizme. Doprinos: 0.13 g, 58%. T.t. 254-256°C. cis-4b,5,9b,10-Tetrahydro-5-acetyl-3,7d-dinitroindeno[1,2-b]indole (0.4 g, 1.2 mM) was mixed in a solution of glacial acetic acid (30 cm3) and water ( 5 cm3). To this mixture was added titanium trichloride (3 cm3 of a 30% solution in 24% aqueous hydrochloric acid) for 5 minutes. After another 2 hours, the reaction mixture became colorless and more (0.5 cm3) of titanium trichloride reagent was added. The unreacted starting material was filtered off (0.13 g) and the filtrate was poured over crushed ice. The pH of the solution thus obtained was adjusted to 6 (15 cm3, 0.89 ammonia) and the product was extracted with ethyl acetate (8 x 50 cm3). This extraction was very slow, because the emulsion is building, so it took 3 days. The extracts were combined and evaporated to give a greenish solid which was triturated with diethyl ether to give colorless microprisms. Contribution: 0.13 g, 58%. T.t. 254-256°C.

Primjer 44 Example 44

cis-4b,5,9b,10-Tetrahidro-5-acetil-3,7di-(N,N-dietilamino)indeno[1,2-b]indol cis-4b,5,9b,10-Tetrahydro-5-acetyl-3,7di-(N,N-diethylamino)indeno[1,2-b]indole

cis-4b,5,9b,10-Tetrahidro-5-acetil-3,7d-diaminoindeno[1,2-b]indol (0.13 g) je otopljeno u tetrahidrofuranu (18 cm3) koji sadrži vodu (3.5 cm3), natrijevog karbonata (0.3 g) i etil jodid (0.8 cm3), pa je zagrijavan 24 sata na refluksu. Zatim je dodana dodatna količina etil jodida (0.8 cm3) i zagrijavanje je nastavljeno još 4 sata. Otapala i višak reagensa su uklonjeni i ostatak je ekstrahiran s eterom (6 x 10 cm3). Kombinirani ekstrakti su isparavani da bi dali smeđu gumu (0.33 g) koja je pročišćena kromatografijom na koloni silikagela (4 g) uz eluiranje sa 20% etil acetatom u 60-80°C petrol eteru. Dobiven je naslovni spoj u obliku bezbojnih prizmi. Doprinos: 0.023 g, 12.5%. T.t. 137-138°C. cis-4b,5,9b,10-Tetrahydro-5-acetyl-3,7d-diaminoindeno[1,2-b]indole (0.13 g) was dissolved in tetrahydrofuran (18 cm3) containing water (3.5 cm3), sodium carbonate (0.3 g) and ethyl iodide (0.8 cm3), so it was heated for 24 hours at reflux. An additional amount of ethyl iodide (0.8 cm3) was then added and heating was continued for another 4 hours. Solvents and excess reagents were removed and the residue was extracted with ether (6 x 10 cm3). The combined extracts were evaporated to give a brown gum (0.33 g) which was purified by silica gel column chromatography (4 g) eluting with 20% ethyl acetate in 60-80°C petroleum ether. The title compound was obtained in the form of colorless prisms. Contribution: 0.023 g, 12.5%. T.t. 137-138°C.

1H NMR (CDCl3) δ : 4 x [1.12 (6H, t, J=7.0Hz)], 2.50 and 2.57 2 x [3H, s)], 3.5 (1H, d, J=16.5Hz), 3.10 (1H, d, J=16.0Hz), 3.26 and 3.30 4 x [4H, q, J=7.0Hz)] 3.98 (1H, dd, J=7.5 and 7.5Hz), 4.07 (1H, dd, J=7.5 and 7.0Hz), 5.70 (1, d, J=7.5Hz), 6.23 (1H, d, J=7.0Hz), 6.32-6.40 (2H, m), 6.59 (2H, ddd, J=8.0, 1.5Hz), 6.96 (2H, d, J=1.0Hz), 6.95-7.10 (5H, m), 7.61 (1H, d, J=1.5Hz). 1H NMR (CDCl3) δ : 4 x [1.12 (6H, t, J=7.0Hz)], 2.50 and 2.57 2 x [3H, s)], 3.5 (1H, d, J=16.5Hz), 3.10 (1H , d, J=16.0Hz), 3.26 and 3.30 4 x [4H, q, J=7.0Hz)] 3.98 (1H, dd, J=7.5 and 7.5Hz), 4.07 (1H, dd, J=7.5 and 7.0 Hz), 5.70 (1, d, J=7.5Hz), 6.23 (1H, d, J=7.0Hz), 6.32-6.40 (2H, m), 6.59 (2H, ddd, J=8.0, 1.5Hz), 6.96 (2H, d, J=1.0Hz), 6.95-7.10 (5H, m), 7.61 (1H, d, J=1.5Hz).

Primjer 45 Example 45

cis-5,5a,6,10b-Tetrahidro-9-metoksiindeno[2,1-b]indol cis-5,5a,6,10b-Tetrahydro-9-methoxyindeno[2,1-b]indole

5,6-Dihidro-9-metiksiindeno[2,1-b]indol (0.56 g) je, kao suspenzija u glacijalnoj octenoj kiselini (25 cm3) na 16°C, tretiran s natrijevim cijanoborohidridom (1.0 g) u malim količinama, tokom 6 sati. Dobivena otopina je miješana još jedan sat i zatim je prosuta u led/vodu (100 cm3). Otopina je odvojena od male količine smolastog materijala i filtrat je tretiran s natrijevim karbonatom (2.5 g) u malim količinama i uz jako miješanje. Odvojena bezbojna kruta supstancija je prikupljena i kristalizirana iz etanola u obliku iglica. Doprinos: 0.31 g, 55% M.p. 129-130°C. 5,6-Dihydro-9-methoxyindeno[2,1-b]indole (0.56 g) was, as a suspension in glacial acetic acid (25 cm3) at 16°C, treated with sodium cyanoborohydride (1.0 g) in small amounts, during 6 hours. The resulting solution was stirred for another hour and then poured into ice/water (100 cm3). The solution was separated from a small amount of resinous material and the filtrate was treated with sodium carbonate (2.5 g) in small amounts and with vigorous stirring. The separated colorless solid was collected and crystallized from ethanol in the form of needles. Contribution: 0.31 g, 55% M.p. 129-130°C.

1H NMR (CDCl3) δ : 3.06 (1H, dd, J=16.5 and 1.5Hz), 3.2-3.8 (1H, br. s), 3.31 (1H, dd, J=16.5 and 6.0Hz), 3.76 (3H, s), 4.71 (1H, d, J=8.0Hz), 4.80Hz), 4.80 (1H, ddd, J=8.0, 6.0 and 2.0Hz), 6.5 (1H, d, J=8.5Hz) 6.58 (1H, dd, J=8.5 and 2.5Hz), 6.99 (1H, d, J=2.5Hz), 7.15-7.24 (3H, m), 7.33-7.36 (1H, m). 1H NMR (CDCl3) δ : 3.06 (1H, dd, J=16.5 and 1.5Hz), 3.2-3.8 (1H, no. s), 3.31 (1H, dd, J=16.5 and 6.0Hz), 3.76 (3H, s), 4.71 (1H, d, J=8.0Hz), 4.80Hz), 4.80 (1H, ddd, J=8.0, 6.0 and 2.0Hz), 6.5 (1H, d, J=8.5Hz) 6.58 (1H, dd, J=8.5 and 2.5Hz), 6.99 (1H, d, J=2.5Hz), 7.15-7.24 (3H, m), 7.33-7.36 (1H, m).

Primjer 46 Example 46

cis-5,5a,6,10b-Tetrahidro-9-izopropilindeno[2,1-b]indol i cis-5,5a,6,10b-Tetrahydro-9-isopropylindeno[2,1-b]indole and

Suspenziji 5,6-dihidro-9-izopropilindeno[2,1-b]indola (2.3 g, 9.3 mmol) u glacijalnoj octenoj kiselini (30 cm3) dodan je natrijev cijanoborohidrid (2 g) u malim količinama, tokom 30 minuta. Smjesa je miješana 3 sata i otopina koja je tako dobivena je izlivena preko led/vode (50 cm3) i miješana 1 sat. Bistra otopina je pažljivo neutralizirana sa natrijevim hidroksidom, što je izazvalo pojavu bijelog taloga. Ovaj talog je ekstrahiran dietil eterom (3 x 10 cm3), pa su kombinirani ekstrakti isprani više puta s vodom, sušeni (Na2SO4) i isprani. TLC analiza ostatka je pokazala da se radi o dva proizvoda, koji su izolirani kromatografijom na koloni uz eluiranje sa 10% etil acetatom u 60-80°C petrol eteru da bi se prvo dobila mala količina cis.5,5a,6,10-tetrahidro-6-etil-9-izopropilindeno[2,1-b]indola (0.07 g, 3%), a zatim i naslovni spoj (0.93 g, 40%), oba kao bezbojna ulja. Daljnje prečišćavanje ovog drugog proizvoda izvršeno je destilacijom. To a suspension of 5,6-dihydro-9-isopropylindeno[2,1-b]indole (2.3 g, 9.3 mmol) in glacial acetic acid (30 cm3) was added sodium cyanoborohydride (2 g) in small amounts over 30 minutes. The mixture was stirred for 3 hours and the solution thus obtained was poured over ice/water (50 cm3) and stirred for 1 hour. The clear solution was carefully neutralized with sodium hydroxide, which caused the appearance of a white precipitate. This precipitate was extracted with diethyl ether (3 x 10 cm 3 ), and the combined extracts were washed several times with water, dried (Na 2 SO 4 ) and washed. TLC analysis of the residue showed that it was two products, which were isolated by column chromatography eluting with 10% ethyl acetate in 60-80°C petroleum ether to first obtain a small amount of cis.5,5a,6,10- tetrahydro-6-ethyl-9-isopropylindeno[2,1-b]indole (0.07 g, 3%) and then the title compound (0.93 g, 40%), both as colorless oils. Further purification of this second product was carried out by distillation.

1H NMR (CDCl3) δ : 7.4-7.1 (5H, m), 6.87 (1H, dd, J=8.1Hz), 6.50 (1H, d, J=8.1Hz), 4.81 (1H, ddd, J=8.1, 6.2 and 2.0Hz), 4.73 (1H, d, J=8.1Hz), 3.32 (1H, dd, J=16.6 and 6.2), 3.08 (1H, dd, J=16.6 and 2.0Hz), 2.83 (1H, septet, J=6.9Hz), 1.23 (6H, d, 6.9Hz). 1H NMR (CDCl3) δ : 7.4-7.1 (5H, m), 6.87 (1H, dd, J=8.1Hz), 6.50 (1H, d, J=8.1Hz), 4.81 (1H, ddd, J=8.1, 6.2 and 2.0Hz), 4.73 (1H, d, J=8.1Hz), 3.32 (1H, dd, J=16.6 and 6.2), 3.08 (1H, dd, J=16.6 and 2.0Hz), 2.83 (1H, septet , J=6.9Hz), 1.23 (6H, d, 6.9Hz).

Primjer 47 Example 47

5,6-Dihidro-9-fluoroindeno[2,1-b]indol (0.55 g, 2.5 mM) u glacijalnoj octenoj kiselini (25 cm3) miješan je i tretiran cijanoborohidridom (2.1 g, 36.5 mM) u malim količinama, tokom 10 sati, uz održavanje temperature ispod 18°C. Izgleda da je količina redukcijskog sredstva vrlo bitna, jer se, ukoliko se doda veća količina, formiraju smjese. Reakcijska smjesa je zatim izdvojena u led/vodu (100 cm3) i formirano žuto ulje je odvojeno od vodene faze. pH vodene faze je namješteno na 6 dodatkom natrijevog karbonata (30 g), pa je bezbojno ulje koje se oslobodilo ekstrahirao dietil eterom (4 x 20 cm3). Kombinirai ekstrakti su sušeni i ispareni, da bi dali ulje koje je ekstrahirano s vrućim 60-80°C petrol eterom (6 x 10 cm3), nakon čega je ostatak trituriran s etanolom (1 cm3). ovo tretiranje je izazvalo kristalizaciju bezbojnih prizmi koje, nakon prekristalizacije iz etanola, daju naslovni spoj. Doprinos: 60 mg, 11% T.t. 116-117°C. 5,6-Dihydro-9-fluoroindeno[2,1-b]indole (0.55 g, 2.5 mM) in glacial acetic acid (25 cm3) was stirred and treated with cyanoborohydride (2.1 g, 36.5 mM) in small amounts over 10 hours, while keeping the temperature below 18°C. It seems that the amount of reducing agent is very important, because if a larger amount is added, mixtures are formed. The reaction mixture was then partitioned into ice/water (100 cm3) and the yellow oil formed was separated from the aqueous phase. The pH of the aqueous phase was adjusted to 6 by adding sodium carbonate (30 g), so the colorless oil that was released was extracted with diethyl ether (4 x 20 cm3). The combined extracts were dried and evaporated to give an oil which was extracted with hot 60-80°C petroleum ether (6 x 10 cm3), after which the residue was triturated with ethanol (1 cm3). this treatment caused the crystallization of colorless prisms which, after recrystallization from ethanol, gave the title compound. Contribution: 60 mg, 11% T.t. 116-117°C.

1H NMR (CDCl3) δ : 3.06 (1H, dd, J=16.5 and 1.5Hz), 3.31 (1H, dd, J=16.5 and 6.0Hz), 3.67 (1H, br. s), 4.70 (1H, d, J=8.0Hz), 4.82 (1H, ddd, J=8.0, 6.0 and 1.5Hz), 6.43 (1H, dd, J=8.5 and 4.0Hz), 6.70 (1H, ddd, J=8.5, 8.5 and 2.5Hz), 7.07 (1H, dd, J=8.5 and 2.5Hz), 7.16-7.25 (3H, m), 7.33 (1H, m). 1H NMR (CDCl3) δ : 3.06 (1H, dd, J=16.5 and 1.5Hz), 3.31 (1H, dd, J=16.5 and 6.0Hz), 3.67 (1H, no. s), 4.70 (1H, d, J=8.0Hz), 4.82 (1H, ddd, J=8.0, 6.0 and 1.5Hz), 6.43 (1H, dd, J=8.5 and 4.0Hz), 6.70 (1H, ddd, J=8.5, 8.5 and 2.5Hz ), 7.07 (1H, dd, J=8.5 and 2.5Hz), 7.16-7.25 (3H, m), 7.33 (1H, m).

Primjer 48 Example 48

cis-9-Terc-butil-5,5a,6,10b-tetrahidroindeno[2,1-b]indol cis-9-tert-butyl-5,5a,6,10b-tetrahydroindeno[2,1-b]indole

9-Terc-butil-5,6-dihidroindeno[2,1-b]indol 0.16 g, 0.6 mM) u glacijalnoj octenoj kiselini (25 cm3) miješan je i tretiran s natrijevim cijanoborohidridom (0.7 g, 11 mM) u malim količinama, tokom 3 sata, uz održavanje temperature ispod 18°C. Reakcijska smjesa je zatim prosuta u led/vodu 880 cm3), pa je formirano žuto ulje odvojeno od vodene faze. pH vodene faze je namješteno na 6 dodatkom natrijevog karbonata (25 g), pa je oslobođeno bezbojno ulje ekstrahirano sa dietil eterom (6 x 10 cm3). Kombinirani su ekstrakti sušeni i ispareni da bi dali ulje koje je kromatografirano na silikagelu uz eluiranje sa 5% etil acetata u 60-80°C petrol eteru. Dobiven je naslovni spoj u obliku bezbojnih prizmi. Doprinos: 0.11 g, 7% T.T. 92°C; 9-tert-butyl-5,6-dihydroindeno[2,1-b]indole 0.16 g, 0.6 mM) in glacial acetic acid (25 cm3) was mixed and treated with sodium cyanoborohydride (0.7 g, 11 mM) in small amounts , during 3 hours, while maintaining the temperature below 18°C. The reaction mixture was then poured into ice/water (880 cm3) and a yellow oil separated from the aqueous phase was formed. The pH of the aqueous phase was adjusted to 6 by the addition of sodium carbonate (25 g), and the released colorless oil was extracted with diethyl ether (6 x 10 cm3). The combined extracts were dried and evaporated to give an oil which was chromatographed on silica gel eluting with 5% ethyl acetate in 60-80°C petroleum ether. The title compound was obtained in the form of colorless prisms. Contribution: 0.11 g, 7% T.T. 92°C;

1H NMR (CDCl3) δ : 1.30 (9H, s), 3.05 (1H, d, J=16.5Hz), 3.28 (1H, dd, J=16.5 and 6.0Hz), 3.79 (1H, s), 4.70 (1H, d, J=8.0Hz), 4.75 (1H, ddd, J=8.0, 6.0 and 2.0Hz), 6.48 (1H, d, J=8.0Hz), 7.03 (1H, dd, J=8.0 and 2.0Hz), 7.14-724 (3H, m), 7.34 (1H, m), 7.40 (1H, d, J=2.0Hz). 1H NMR (CDCl3) δ : 1.30 (9H, s), 3.05 (1H, d, J=16.5Hz), 3.28 (1H, dd, J=16.5 and 6.0Hz), 3.79 (1H, s), 4.70 (1H , d, J=8.0Hz), 4.75 (1H, ddd, J=8.0, 6.0 and 2.0Hz), 6.48 (1H, d, J=8.0Hz), 7.03 (1H, dd, J=8.0 and 2.0Hz) , 7.14-724 (3H, m), 7.34 (1H, m), 7.40 (1H, d, J=2.0Hz).

Primjer 49 Example 49

9b,10-Dihidro-9b-metilindeno[1,2-b]indol 9b,10-Dihydro-9b-methylindeno[1,2-b]indole

Balon sušen na plamenu napunjen je otopinom fenilhidrazona 2-metil-1-indanona (1.47 g, 6.22 mmol) u DCM (30 cm3) i zatim fosfor trikloridom (3.4 cm3 2.OM otopine u DCM). Otopina je zagrijavana do refluksa tokom 2 sata, ohlađena je i izlivena u zasićenu otopinu natrijevog hidrogenkarbonata. Nakon 1 sat miješanja, organski materijal je ekstrahiran s još DCM. Bazne komponente su ponovo ekstrahirane sa 2M otopinom klorovodikove kiseline. Ova vodena otopina je alkalizirana, pa je ponovno ekstrahirana sa DCM. Isparavanje otapala pod vakuumom i kromatografija ostatka na koloni (20% EtOAc/60-80°C petrol eter) dali su bistru gumu (Rf [10% EtOAc/petrol eter] 0.1), koja se može dalje pročistiti destilacijom iz balona u balon, čime se dobiva naslovni spoj kao guma. Doprinos: 0.4 g (30%). T.vr. 170°C (0.2 mm Hg). A flame-dried flask was charged with a solution of phenylhydrazone 2-methyl-1-indanone (1.47 g, 6.22 mmol) in DCM (30 cm3) and then phosphorus trichloride (3.4 cm3 of a 2.OM solution in DCM). The solution was heated to reflux for 2 hours, cooled and poured into a saturated sodium bicarbonate solution. After stirring for 1 hour, the organic material was extracted with more DCM. The base components were re-extracted with 2M hydrochloric acid solution. This aqueous solution was alkalized, so it was re-extracted with DCM. Evaporation of the solvent under vacuum and column chromatography of the residue (20% EtOAc/60-80°C petroleum ether) gave a clear gum (Rf [10% EtOAc/petroleum ether] 0.1), which could be further purified by flask-to-flask distillation, thus obtaining the title compound as rubber. Contribution: 0.4 g (30%). T.vr. 170°C (0.2 mm Hg).

1H NMR (CDCl3) δ : 1.39 (3H, s), 2.84 (1H, d), 3.11 (3H, d), 6.4, 8.4 (8H, m). 1H NMR (CDCl3) δ: 1.39 (3H, s), 2.84 (1H, d), 3.11 (3H, d), 6.4, 8.4 (8H, m).

Primjer 50 Example 50

cis-9b,10-Dihidro-8,9b-dimetilindeno[1,2-b]indol cis-9b,10-Dihydro-8,9b-dimethylindeno[1,2-b]indole

Otopini 4-metilfenilhidrazin klorohidrata (9.73 g, 0.06 mmol) u aposlutnom etanolu (240 cm3) u kapima je dodan 2-metil-1-indanon (8.14 g, 0.056 mmol) i zatim koncentrirana klorovodikova kiselina (3 cm3). Smjesa je vrila tokom 2 sata, otapala su uklonjena, pa je ostatak podijeljen između dietil etera i vode, a slojevi su odvojeni. Vodena faza je ekstrahirana sa dietil eterom (3 x 50 cm3). Kombinirane organske faze su isprane najprije sa zasićenom otopinom natrijevog bikarbonata, a zatim sa slanom otopinom, te su sušene i isparavane. Tako dobiven sirovi materijal pročišćen je fleš-kromatografijom na silikagelu, uz eluiranje sa 7-12% etil acetatu u 60-80°C petrol eteru da bi se dobila kruta supstancija (5.05 g, 39%). To a solution of 4-methylphenylhydrazine chlorohydrate (9.73 g, 0.06 mmol) in absolute ethanol (240 cm3) was added dropwise 2-methyl-1-indanone (8.14 g, 0.056 mmol) and then concentrated hydrochloric acid (3 cm3). The mixture was boiled for 2 hours, the solvents were removed, and the residue was partitioned between diethyl ether and water, and the layers were separated. The aqueous phase was extracted with diethyl ether (3 x 50 cm3). The combined organic phases were washed first with saturated sodium bicarbonate solution and then with brine, dried and evaporated. The crude material thus obtained was purified by flash chromatography on silica gel, eluting with 7-12% ethyl acetate in 60-80°C petroleum ether to obtain a solid substance (5.05 g, 39%).

1H NMR (CDCl3) δ : 7.87 (1H, m) 7.51 (1H, d, J=7.9Hz) 7.39 (3H, m) 7.25 (1H, s), 7.15 (1H, d, J=8.0Hz) 3.07 (1H, d, J=14.7Hz) 2.81 (1H, d, J=14.7Hz) 2.41 (3H, s) 7.37 (3H, s). 1H NMR (CDCl3) δ : 7.87 (1H, m) 7.51 (1H, d, J=7.9Hz) 7.39 (3H, m) 7.25 (1H, s), 7.15 (1H, d, J=8.0Hz) 3.07 ( 1H, d, J=14.7Hz) 2.81 (1H, d, J=14.7Hz) 2.41 (3H, s) 7.37 (3H, s).

Primjer 51 Example 51

9b,10-Dihidro-9b-metil-izopropilindeno[1,2-b]indol 9b,10-Dihydro-9b-methyl-isopropylindeno[1,2-b]indole

Otopini 4-izopropilfenilhidrazin klorohidrata (6.50 g, 0.035 mmol) u aposlutnom etanolu (140 cm3) u kapima je dodan 2-metil-1-indanon (4.6 g, 0.032 mmol) i zatim koncentrirana klorovodikova kiselina (2.5 cm3). Smjesa je refluksirana 2 sata i etanol je isparen. Ostatak je podijeljen između dietil etera (100 cm3) i vode (100 cm3), pa su slojevi odvojeni. Vodena faza je ekstrahirana sa dietil eterom (2 x 30 cm3) i organski ekstrakti su isprani najprije sa zasićenom otopinom natrijevog bikarbonata i zatim sa slanom otopinom, pa su sušeni (Na2SO4). Uklanjanje otapala dalo je naslovni spoj koji je pročišćen fleš-kromatografijom na silikagelu, uz eluiranje sa 10% etil acetatom u 60-80°C petrol eteru, čime je dobivena žuta guma; 1.62 g, 25%; To a solution of 4-isopropylphenylhydrazine chlorohydrate (6.50 g, 0.035 mmol) in absolute ethanol (140 cm3) was added dropwise 2-methyl-1-indanone (4.6 g, 0.032 mmol) and then concentrated hydrochloric acid (2.5 cm3). The mixture was refluxed for 2 hours and the ethanol was evaporated. The residue was partitioned between diethyl ether (100 cm3) and water (100 cm3), and the layers were separated. The aqueous phase was extracted with diethyl ether (2 x 30 cm3) and the organic extracts were washed first with saturated sodium bicarbonate solution and then with brine, then dried (Na2SO4). Removal of the solvent gave the title compound which was purified by flash chromatography on silica gel eluting with 10% ethyl acetate in 60-80°C petroleum ether to give a yellow gum; 1.62 g, 25%;

1H NMR (CDCl3) δ : 7.88 (1H, m) 7.55 (1H, d, J=8.1Hz) 7.41 (3H, m) 7.30 (1H, d, J=1.8Hz) 7.23 (1H, dd, J=1.8 and 7.1 Hz) 3.10 (1H, d, J=14.7Hz) 2.98 (1H, septet, J=7.0Hz) 2.85 (1H, d, J=14.7Hz) 1.39 (3H, s) 1.30 (6H, d, J=7.0Hz). 1H NMR (CDCl3) δ : 7.88 (1H, m) 7.55 (1H, d, J=8.1Hz) 7.41 (3H, m) 7.30 (1H, d, J=1.8Hz) 7.23 (1H, dd, J=1.8 and 7.1 Hz) 3.10 (1H, d, J=14.7Hz) 2.98 (1H, septet, J=7.0Hz) 2.85 (1H, d, J=14.7Hz) 1.39 (3H, s) 1.30 (6H, d, J =7.0Hz).

Početne tvari, derivati DHII i izo-DHII, detaljnije su ilustrirane u primjerima paralelne patentne prijave. The starting materials, DHII and iso-DHII derivatives, are illustrated in more detail in the examples of the parallel patent application.

Primjer 52 Example 52

cis-(E)- i (Z)-5-Acetil-8-amino-4b,5,9b,10-tetrahidroindeno[1,2-b]indol cis-(E)- and (Z)-5-Acetyl-8-amino-4b,5,9b,10-tetrahydroindeno[1,2-b]indole

(E)- i (Z)-Acetil-8-nitro-4b,5,9b,10-tetrahidroindeno[1,2-b]indol (4.2 g) u glacijalnoj octenoj kiselini (250 cm3) i vodi (25 cm3) miješan je i tretiran sa 30% vodenom otopinom titan triklorida (42 cm3) tokom 5 minuta. Nakon još 15 minuta, reakcijska smjesa je prosuta u led i vodu (800 cm3) i pH otopine je namješten na 4.5 dodtkom amonijevog hidroksida. Proizvod je zatim što je brže moguće ekstrahiran sa diklorometanom (6 x 75 cm3). Kombinirani ekstrakti su sušeni i ispareni da bi dali krutu supstanciju koja je trituirana sa dietil eterom da bi dala naslovni spoj u obliku bezbojne krute supstancije. Doprinos: 2.0 g, 77%. T.t. 196-198°C. (E)- and (Z)-Acetyl-8-nitro-4b,5,9b,10-tetrahydroindeno[1,2-b]indole (4.2 g) in glacial acetic acid (250 cm3) and water (25 cm3) it was mixed and treated with a 30% aqueous solution of titanium trichloride (42 cm3) for 5 minutes. After another 15 minutes, the reaction mixture was poured into ice and water (800 cm3) and the pH of the solution was adjusted to 4.5 by the addition of ammonium hydroxide. The product was then extracted as quickly as possible with dichloromethane (6 x 75 cm3). The combined extracts were dried and evaporated to give a solid which was triturated with diethyl ether to give the title compound as a colorless solid. Contribution: 2.0 g, 77%. T.t. 196-198°C.

1H NMR δ : (3H, s), 2.55 (3H,), 3.16 (1H, d, J=16Hz), 3.22 (1H, d, J=16Hz), 3.45 (1H, m), 3.65 (4H, exchanged by D20), 4.01 (1H, dd, J==8Hz), 4.13 (1H, dd, J==7.5Hz), 5.72 (1H, d,), 6.26 (1H, d, J=8Hz), 6.46 (2H, d, J=8.5Hz), 6.57 (1H, s), 6.64 (1H,), 6.82 (1h, d, J=8.5Hz), 7.16-7.25 (6H, m), 7.38 (1H, d, J=7.5Hz), 7.64 (1H, d, J=7.5Hz), 7.85 (1H, d, J=8.5Hz). 1H NMR δ : (3H, s), 2.55 (3H,), 3.16 (1H, d, J=16Hz), 3.22 (1H, d, J=16Hz), 3.45 (1H, m), 3.65 (4H, exchanged by D20), 4.01 (1H, dd, J==8Hz), 4.13 (1H, dd, J==7.5Hz), 5.72 (1H, d,), 6.26 (1H, d, J=8Hz), 6.46 ( 2H, d, J=8.5Hz), 6.57 (1H, s), 6.64 (1H,), 6.82 (1h, d, J=8.5Hz), 7.16-7.25 (6H, m), 7.38 (1H, d, J=7.5Hz), 7.64 (1H, d, J=7.5Hz), 7.85 (1H, d, J=8.5Hz).

Naslovni spoj može se dobiti u sličnom doprinosu katalitičkom hidrogenacijom smjese izomernih nitro spojeva preko 10% paladija na ugljenu kao katalizatora, uz korištenje kloroforma kao otopine. The title compound can be obtained in a similar manner by catalytic hydrogenation of a mixture of isomeric nitro compounds over 10% palladium on charcoal as a catalyst, using chloroform as a solution.

Primjer 53 Example 53

cis-(E)- i (Z)-5-Acetil-8-(N-acetilamino)-4b,5,9b,10-tetrahidroindeno[1,2-b]indol cis-(E)- and (Z)-5-Acetyl-8-(N-acetylamino)-4b,5,9b,10-tetrahydroindeno[1,2-b]indole

Smjesa cis-(E)- i (Z)-5-acetil-8-amino-4b,5,9b,10-tetrahidroindeno[1,2-b]indola iz Primjera 52 acetilirana je na uobičajeni način, da bi se dobili naslovni spojevi. [Nađeno: C, 74.1; H. 5.8; N, 9.0. C19H18N2O2 zahtjeva: C, 74.5; H, 5.9; N, 9.2] A mixture of cis-(E)- and (Z)-5-acetyl-8-amino-4b,5,9b,10-tetrahydroindeno[1,2-b]indole from Example 52 was acetylated in the usual manner to give title compounds. [Found: C, 74.1; H. 5.8; N, 9.0. C19H18N2O2 required: C, 74.5; H, 5.9; N, 9.2]

Primjer 54 Example 54

cis-4b,5,9b,10-tetrahidro-4,6-dimetil-8-metoksiindeno[1,2-b]indol cis-4b,5,9b,10-tetrahydro-4,6-dimethyl-8-methoxyindeno[1,2-b]indole

(i) 4-Hidrazino-3-metilanizol klorohidrat (i) 4-Hydrazino-3-methylanisole chlorohydrate

33 g (0.19 mol) 4-metoksi-metilanilin klorohidrata suspendirano je u 100 ml (6 M) klorovodikove kiseine pod atmosferom argona. Smjesa je ohlađena na +5°C i u kapima je dodana otopina 13.1 g (0.19 mol) NaNO2 u 35 ml vode, takvom brzinom da temperatura ne naraste preko +5°C. Po završetku dodavanja otopina je miješana 30 minuta na +5°C. 101.7 g (0.58 mol) Na2S2O4 otopljeno je u 500 ml vode na +5°C, otopina je prosuta u reakcijsku smjesu, pa je miješanje nastavljeno još 10 min. 33 g (0.19 mol) of 4-methoxy-methylaniline chlorohydrate was suspended in 100 ml (6 M) of hydrochloric acid under an argon atmosphere. The mixture was cooled to +5°C and a solution of 13.1 g (0.19 mol) NaNO2 in 35 ml of water was added dropwise, at such a rate that the temperature did not rise above +5°C. After the addition, the solution was stirred for 30 minutes at +5°C. 101.7 g (0.58 mol) of Na2S2O4 was dissolved in 500 ml of water at +5°C, the solution was poured into the reaction mixture, and the mixing was continued for another 10 min.

Dodano je 250 ml dietil etera, pa je smjesa alkalizirana s NaOH (10 M) do pH 9. Faze su odvojene i vodena faza je ekstrahirana s dietil eterom. Kombinirane organske faze su isprane vodenom otopinom NaHCO3 i sušene sa Na2SO4. Eterska faza je filtrirana kroz celit. Otopini proizvoda dodana je zasićena otopina plinovitog HCl u eteru, pa je staložena klorohidratna sol hidrazina. 250 ml of diethyl ether was added, and the mixture was alkalized with NaOH (10 M) to pH 9. The phases were separated and the aqueous phase was extracted with diethyl ether. The combined organic phases were washed with aqueous NaHCO3 and dried with Na2SO4. The ether phase was filtered through celite. A saturated solution of gaseous HCl in ether was added to the product solution, and the chlorohydrate salt of hydrazine was precipitated.

Kristali su prikupljeni na vakuumskom lijevku i isprani dietil eterom i kloroformom. Izolirano je 29.5 g (82%) proizvoda. The crystals were collected on a vacuum funnel and washed with diethyl ether and chloroform. 29.5 g (82%) of the product was isolated.

(ii) 5,10-Dihidro-4,6-dimetil-8-metoksiindeno[1,2-b]indol (ii) 5,10-Dihydro-4,6-dimethyl-8-methoxyindeno[1,2-b]indole

U balon je dodano 130 ml etanola, zasićena otopina plinovitog Hcl u 130 ml etera, 5.8 g (21 mmol) 4-hidrazino-3-metilanizol klorohidrata i 4.8 g (31 mmol) 7-metil-1-indanona. Otopina je miješana preko noći na sobnoj temperaturi. U reakcijskoj smjesi zaostalo je nešto 7-metil-1-indanona. Dodan je višak 4-hidrazino-3-metilanizol klorohidrata (0.6 g), pa je otopina ponovo promiješana preko noći. Otapalo je ispareno i sirovi proizvod je otopljen u eteru, pa je ispran dva puta sa 1 M otopinom NaOH i zatim sa vodom. Organska faza je sušena sa Na2SO4., filtrirana i isparena. Preostalo je ulje koje je kromatografirano i eluirano diklorometanom. Izolirano je 1.3 g (16%) proizvoda. 130 ml of ethanol, a saturated solution of gaseous HCl in 130 ml of ether, 5.8 g (21 mmol) of 4-hydrazino-3-methylanisole chlorohydrate and 4.8 g (31 mmol) of 7-methyl-1-indanone were added to the flask. The solution was stirred overnight at room temperature. Some 7-methyl-1-indanone remained in the reaction mixture. An excess of 4-hydrazino-3-methylanisole chlorohydrate (0.6 g) was added, and the solution was again stirred overnight. The solvent was evaporated and the crude product was dissolved in ether, then washed twice with 1 M NaOH solution and then with water. The organic phase was dried with Na2SO4, filtered and evaporated. The remaining oil was chromatographed and eluted with dichloromethane. 1.3 g (16%) of the product was isolated.

(iii) Cis-4b,5,9b,10-tetrahidro-4,6-dimetil-8-metoksiindeno[1,2-b]indol (iii) Cis-4b,5,9b,10-tetrahydro-4,6-dimethyl-8-methoxyindeno[1,2-b]indole

U balon s okruglim dnom dodano je 16 ml dioksana, 1.3 g (4.9 mmol) 5,10-dihidro- 4,6-dimetil-8- metoksiindeno [1,2-b]indola i 1.98 g (19.6 mmol) morfolinborana. U kapima je, tokom miješanja otopine, dodano 4 ml konc. klorovodikove kiseline. Reakcijska smjesa je refluksirana 1 sat . Dodano je 8 ml 6 M klorovodikove kiseline, pa je smjesa refluksirana 30 minuta. Nakon što se otopina ohladila do sobne temperature, dodano je 50 ml vode. Smjesa je alkalizirana s vodenom otopinom NaOH do pH 9. Proizvod je dva puta ekstrahiran diklorometanom. Organska faza je sušena sa Na2SO4 i otapalo je ispareno. Proizvod je dva puta ekstrahiran diklorometanom. Organska faza je suđena sa Na2SO4 i otopina je isparena. Proizvod je podvrgnut kromatografiji uz eluiranje diklorometanom. Izolirani proizvod je otopljen u acetonitrilu, dodana je zasićena otopina plinovitog HCl u eteru, pa je proizvod staložen u obliku klorohidratne soli koja je izolirana filtriranjem. Dobiveno je 1.2 g (82.2%) proizvoda. 16 ml of dioxane, 1.3 g (4.9 mmol) of 5,10-dihydro-4,6-dimethyl-8-methoxyindene [1,2-b]indole and 1.98 g (19.6 mmol) of morpholinborane were added to a round-bottom flask. During the mixing of the solution, 4 ml of conc. hydrochloric acid. The reaction mixture was refluxed for 1 hour. 8 ml of 6 M hydrochloric acid was added, and the mixture was refluxed for 30 minutes. After the solution cooled to room temperature, 50 ml of water was added. The mixture was alkalized with aqueous NaOH to pH 9. The product was extracted twice with dichloromethane. The organic phase was dried with Na2SO4 and the solvent was evaporated. The product was extracted twice with dichloromethane. The organic phase was triturated with Na2SO4 and the solution was evaporated. The product was subjected to chromatography eluting with dichloromethane. The isolated product was dissolved in acetonitrile, a saturated solution of gaseous HCl in ether was added, and the product settled in the form of a chlorohydrate salt, which was isolated by filtration. 1.2 g (82.2%) of the product was obtained.

1H NMR (CDCl3) : 2.33 (3H, s), 2.48 (3H, s), 2.95 (1H, dd), 3.56 (1H, dd), 3.77 (3H, s), 4.44 (1H, ddd), 5.71 (1H, d), 6.78 (1H, s), 6.93 (1H, s), 7-11-7.17 (2H, m), 7.30 (1H, d). 1H NMR (CDCl3) : 2.33 (3H, s), 2.48 (3H, s), 2.95 (1H, dd), 3.56 (1H, dd), 3.77 (3H, s), 4.44 (1H, ddd), 5.71 ( 1H, d), 6.78 (1H, s), 6.93 (1H, s), 7-11-7.17 (2H, m), 7.30 (1H, d).

Primjer 55 Example 55

Cis-5,5a,6,10-tetrahidro-7-metil-9-metoksiindeno[2,1-b]indol Cis-5,5a,6,10-tetrahydro-7-methyl-9-methoxyindeno[2,1-b]indole

(i) 4-Hidrazino-3-metilanizol (i) 4-Hydrazino-3-methylanisole

Hlađena, miješana suspenzija 33.0 g (0.19 mol) 2-metil-4-metoksianilin klorohidrata u 100 ml 6N klorovodikove kiseline u kapima je, pod atmosferom argona, tretirana otopinom 13.1 g (0.19 mol) natrijevog nitrita u 35 ml vode. Brzina dodavanja bila je takva da temperatura ne smije prijeći +5°C. Po završetku dodavanja, dobivena smjesa je miješana još 30 minuta na istoj temperaturi. Reakcijska smjesa je zatim, uz miješanje pod atmosferom argona, dodana hlađenoj (+5°C) otopini 101.7 g (0.58 mol) Na2S2O4 u 500 ml vode: Nakon 20 minuta miješanja na toj temperaturi dodano je 250 ml etera, pa je smjesa alkalizirana do pH 9 sa 10 N otopinom natrijevog hidroksida. Organska faza je odvojena i isprana otopinom natrijevog klorida. Nakon sušenja (Na2SO4), tretiranja ugljenom i filtriranja, proizvod je staložen kao u klorohidrat dodatkom zasićene otopine plinovitog HCl u eteru (do pH 3). Filtriranje i ispiranje eterom i kloroformom dalo je 29.6 g (69%) proizvoda. T.t. 105°C. A cooled, stirred suspension of 33.0 g (0.19 mol) of 2-methyl-4-methoxyaniline chlorohydrate in 100 ml of 6N hydrochloric acid in drops was, under an argon atmosphere, treated with a solution of 13.1 g (0.19 mol) of sodium nitrite in 35 ml of water. The rate of addition was such that the temperature should not exceed +5°C. After the addition, the resulting mixture was stirred for another 30 minutes at the same temperature. The reaction mixture was then, with stirring under an argon atmosphere, added to a cooled (+5°C) solution of 101.7 g (0.58 mol) Na2S2O4 in 500 ml of water: After 20 minutes of stirring at that temperature, 250 ml of ether was added, and the mixture was alkalized to pH 9 with 10 N sodium hydroxide solution. The organic phase was separated and washed with sodium chloride solution. After drying (Na2SO4), treatment with charcoal and filtration, the product was precipitated as a chlorohydrate by the addition of a saturated solution of gaseous HCl in ether (up to pH 3). Filtration and washing with ether and chloroform gave 29.6 g (69%) of the product. T.t. 105°C.

(ii) 5,6-Dihidro-7-metil-9-metoksiindeno[1,2-b]indol (ii) 5,6-Dihydro-7-methyl-9-methoxyindeno[1,2-b]indole

Smjesa 1.9 g (0.01 mol) 4-hidrazino-3-metilanizol klorohidrata 1.3 g (0,01 mol) 1-indanona u 25 ml octene kiseline refluksirana je pod atmosferom argona tokom 6 sati. A mixture of 1.9 g (0.01 mol) of 4-hydrazino-3-methylanisole chlorohydrate and 1.3 g (0.01 mol) of 1-indanone in 25 ml of acetic acid was refluxed under an argon atmosphere for 6 hours.

Nakon razblaživanja vodom, dobivena smjesa je ekstrahirana 3 puta s metilen klrodiom. Kombinirane organske faze su isprane 2 puta s 1 M otopinom NaOH, sušene (Na2SO4) i tretirane ugljenom, pa su isparavane da bi dale sirov proizvod. Prečišćavanje na silikagelu, uz korištenje metilen klorida kao eluenta dalo je 0.85 g (34%) proizvoda. T.t. 208°C. After dilution with water, the resulting mixture was extracted 3 times with methylene chloride. The combined organic phases were washed twice with 1 M NaOH solution, dried (Na2SO4) and treated with charcoal, then evaporated to give the crude product. Purification on silica gel using methylene chloride as eluent gave 0.85 g (34%) of the product. T.t. 208°C.

(iii) Cis-5a-5,6,10b-tetrahidro-7-metil-9-metoksiindeno[1,2-b]indol (iii) Cis-5a-5,6,10b-tetrahydro-7-methyl-9-methoxyindeno[1,2-b]indole

Miješanoj suspenziji 0.74 g (0.00296 mol) 5,6-dihidro-7-metil-9-metoksiindeno[1,2-b]indola u 25 ml octene kiseline postepeno je, tokom 5 minuta, dodano 0.93 g (0.0148 mol) NaCNBH3. Smjesa je miješana 3 sata na sobnoj temperaturi, a zatim je razblažena vodom i miješana još 1 sat. Dobivena smjesa je alkalizirana 10 M otopinom NaOH do pH 9, a zatim je 2 puta ekstrahirana eterom. Kombinirane organske faze su 2 puta isprane vodenom otopinom NaCl, pa su sušene (Na2SO4). Nakon isparavanja, ostatak je pročišćen kromatografijom na silikagelu, uz korištenje metilen klorida kao eluenta. Dobiveno je 0.61 g (24%) očekivanog proizvoda T.t. 104°C. 1H NMR (CDCl3) : 2.2 (3H, s), 3.0-3.4 (2H, dd), 3.4-3.5 (1H, bs), 3.75 (3H, s), 4.65-4.80 (2H, m), 6.4-7.4 [6H, m, unutar kojeg 6.45 (1H, dd) i 6.75 (1H, dd)]. To the mixed suspension of 0.74 g (0.00296 mol) of 5,6-dihydro-7-methyl-9-methoxyindeno[1,2-b]indole in 25 ml of acetic acid, 0.93 g (0.0148 mol) of NaCNBH3 was gradually added over 5 minutes. The mixture was stirred for 3 hours at room temperature, then it was diluted with water and stirred for another hour. The resulting mixture was alkalized with a 10 M NaOH solution to pH 9, and then extracted twice with ether. The combined organic phases were washed twice with aqueous NaCl solution and then dried (Na2SO4). After evaporation, the residue was purified by chromatography on silica gel, using methylene chloride as eluent. 0.61 g (24%) of the expected product T.t. was obtained. 104°C. 1H NMR (CDCl3): 2.2 (3H, s), 3.0-3.4 (2H, dd), 3.4-3.5 (1H, bs), 3.75 (3H, s), 4.65-4.80 (2H, m), 6.4-7.4 [6H, m, within which 6.45 (1H, dd) and 6.75 (1H, dd)].

(iv) Racemska smjesa dobivena u stupnju (iii) rastavljena je na enantiomere koji su imali slijedeće fizičko-kemijske osobine: (iv) The racemic mixture obtained in step (iii) was separated into enantiomers that had the following physicochemical properties:

(-) Cis-5,5a,6,10b-tetrahidro-7-metil-9-metoksiindeno[2,1-b]indol (-) Cis-5,5a,6,10b-tetrahydro-7-methyl-9-methoxyindeno[2,1-b]indole

[α]D = -14.5°C (C=1, CH2Cl2) [α]D = -14.5°C (C=1, CH2Cl2)

T.t. 93.5°C. T.t. 93.5°C.

(+)Cis-5,5a,6,10b-tetrahidro-7-metil-9-metoksiindeno[2,1-b]indol (+)Cis-5,5a,6,10b-tetrahydro-7-methyl-9-methoxyindeno[2,1-b]indole

[α]D = -14.5°C (C=1, CH2Cl2) [α]D = -14.5°C (C=1, CH2Cl2)

T.t. 93.5°C. T.t. 93.5°C.

Primjer 56 Example 56

(i) 2-Metil-4-metoksifenilhidrazol 2-metil-1-indanona (i) 2-Methyl-4-methoxyphenylhydrazole 2-methyl-1-indanone

Smjesa 14 g (0.08 mol) 4-hidrazino-3-metilanizola [dobivenog kao što je opisano u Primjeru 55 (i)] i 20 g (0.24 mol) natrijevog acetata u 60 ml vode dobro je izmiješana i zatim filtrirana. Mješanom filtratu dodano je 9.3 g (0.06 mol) 2-metil-1-indanona u 10 ml etanola, što je dovelo do izdvajanja crvenkastog ulja. Nakon hlađenja smjese ulje je kristalizirano. Kristali su prikupljeni i prekristalizirani iz etanola, da bi se dobilo 5.0 g (30%) očekivanog proizvoda. A mixture of 14 g (0.08 mol) of 4-hydrazino-3-methylanisole [prepared as described in Example 55 (i)] and 20 g (0.24 mol) of sodium acetate in 60 ml of water was mixed well and then filtered. To the mixed filtrate was added 9.3 g (0.06 mol) of 2-methyl-1-indanone in 10 ml of ethanol, which led to the separation of a reddish oil. After cooling the mixture, the oil crystallized. The crystals were collected and recrystallized from ethanol to give 5.0 g (30%) of the expected product.

(ii) 9b,10-Dihidro-8-metoksi-6,9b-dimetilindeno[1,2-b]indol (ii) 9b,10-Dihydro-8-methoxy-6,9b-dimethylindeno[1,2-b]indole

Miješanoj otopini hidrazina dobivenog gore u 100 ml etanola dodano je, na temperaturi od 35°C, u toku 15 minuta, 75 ml etera zasićenog klorovodikom. Smjesa je zagrijavana 10 minuta na 35-40°C, pa je ostavljena da se ohladi. Nakon isparavanja otapala ostatak je otopljen u metilen kloridu, isparen razblaženom vodenom otopinom natrijevog klorida i sušen (Na2SO4), pa je isparavan da bi dao 1.7 g (35%) sirovog proizvoda u obliku tamnog ulja. Ovo ulje je bez daljnjeg pročišćavanja korišteno u slijedećem stupnju. To the mixed solution of hydrazine obtained above in 100 ml of ethanol, 75 ml of ether saturated with hydrogen chloride was added at a temperature of 35°C for 15 minutes. The mixture was heated for 10 minutes at 35-40°C, then left to cool. After evaporation of the solvent, the residue was dissolved in methylene chloride, evaporated with dilute aqueous sodium chloride solution and dried (Na2SO4), then evaporated to give 1.7 g (35%) of the crude product as a dark oil. This oil was used in the next stage without further purification.

(iii) Cis-4b,5,9b,10-tetrahidro-8-metoksi-4b,6,9b-trimetilindeno[1,2-b]indol (iii) Cis-4b,5,9b,10-tetrahydro-8-methoxy-4b,6,9b-trimethylindeno[1,2-b]indole

Sirovi materijal (1.7 g, 0.006 mol) dobiven gore otopljen je u 20 ml suhog tetrahidrofurana i ohlađen do -78°C pod atmosferom argona. Miješanoj otopini dodano je 10 ml metillitija (1.6 M) u eteru, nakon čega je smjesa ostavljena da se zagrije do sobne temperature (3 sata). Reakcija je prekinuta dodavanjem smjese etera i zasićene otopine amonijakovog klorida. Organska faza je odvojena, isprana vodom, sušena (Na2SO4) i isparavana. Ostatak je pročišćen kromatografijom na silikagelu, uz korištenje etil acetat/izocijanata(2/8) kao eluenta. Finalno ispiranje dobivenog ulja izooktanom dalo je 0.4 g (24%) proizvoda u obliku bezbojnih kristala. 1H, NMR (CDCl3) : 1.35 (3H, s), 1.5 (2H, s), 2.1 (3H, s), 3.08 (1H, d), 3.38 (d, 1H), 3.7 (3H, s), 6.44 (1H, d), 7.1-7.28 (3H, m), 7.35 (1H, d). The crude material (1.7 g, 0.006 mol) obtained above was dissolved in 20 ml of dry tetrahydrofuran and cooled to -78°C under an argon atmosphere. 10 ml of methyllithium (1.6 M) in ether was added to the mixed solution, after which the mixture was allowed to warm to room temperature (3 hours). The reaction was terminated by adding a mixture of ether and saturated ammonia chloride solution. The organic phase was separated, washed with water, dried (Na2SO4) and evaporated. The residue was purified by chromatography on silica gel, using ethyl acetate/isocyanate (2/8) as eluent. Final washing of the obtained oil with isooctane gave 0.4 g (24%) of the product in the form of colorless crystals. 1H, NMR (CDCl3) : 1.35 (3H, s), 1.5 (2H, s), 2.1 (3H, s), 3.08 (1H, d), 3.38 (d, 1H), 3.7 (3H, s), 6.44 (1H, d), 7.1-7.28 (3H, m), 7.35 (1H, d).

Farmakološke osobine Pharmacological properties

Indenoindoli opisani u sadašnjem izumu predstavljaju hidrofobne i stabilne strukture koje grade katione, stabilne kationske radikale ili radikale nakon oksidacije. Oni predstavljaju jake antioksidanse, kako je izmjereno preko inhibicije lipidne peroksidacije uzrokovane Fe 2+ -askorbatom, in vitro, sa IC50 vrijednosti od čak 10 nM. Spojevi formule IA i IB efikasno sprečavaju oksidaciju lipoproteina u humanoj plazmi u prisutnosti ćelija glatkih mišića zeca ili mišjih perito-nealnih makrofaga. Oni također sprečavaju izokemično/reperfuzijska oštećenja na izoliranom perfundiranom srcu zeca, i štite protiv oštećenja jetre koja su kod miševa izazvana ugljen tetrakloridom acetaminofenonom, metilmetan sulfonatom, menadionom, t-butil hidroperoksidom i N-metil-N1-nitro-N-nitrozoguanidinom. Isto se odnosi na izolirane hepatocite štakora. Ove osobine ukazuju da strukture formula (IA) i (IB) imaju potencijalnu primjenu u profilaksi ili terapiji izokemičnih ili reperfuzionih povreda, naročito cerebralne i srčane izokemije/infarkta, arterioskleroze, tromboze, embolizma, Parkinsonove bolesti, starenja, Alzhajmerove bolesti, neoplazmi i toksičnosti anti-neoplastih lijekova, imunosupresivnih sredstava, kao i zapaljenja uključujući alergijsko/zapaljenska stanja kao što je bronhijalna astma i reumatoidni artritis. Druge potencijalne primjene su u kemoprevenciji protiv kemijske toksičnosti ili oštećenja izazvanih zračenjem. The indenoindoles described in the present invention represent hydrophobic and stable structures that build cations, stable cation radicals or radicals after oxidation. They represent strong antioxidants, as measured by inhibition of lipid peroxidation caused by Fe 2+ -ascorbate, in vitro, with IC50 values as high as 10 nM. Compounds of formulas IA and IB effectively prevent oxidation of lipoproteins in human plasma in the presence of rabbit smooth muscle cells or mouse peritoneal macrophages. They also prevent isochemical/reperfusion injury to the isolated perfused rabbit heart, and protect against liver injury induced in mice by carbon tetrachloride, acetaminophen, methylmethane sulfonate, menadione, t-butyl hydroperoxide, and N-methyl-N1-nitro-N-nitrosoguanidine. The same applies to isolated rat hepatocytes. These properties indicate that the structures of formulas (IA) and (IB) have a potential application in the prophylaxis or therapy of isochemical or reperfusion injuries, especially cerebral and cardiac isochemia/infarction, arteriosclerosis, thrombosis, embolism, Parkinson's disease, aging, Alzheimer's disease, neoplasm and toxicity anti-neoplastic drugs, immunosuppressive agents, as well as inflammation including allergic/inflammatory conditions such as bronchial asthma and rheumatoid arthritis. Other potential applications are in chemoprevention against chemical toxicity or radiation-induced damage.

Indenoindolovi spojevi se ne aktiviraju u značajnijoj mjeri djelovanjem ultraljubičastog zračenja, što ih čini kadidatima za upotrebu u preparatima za njegu kože. Slijedeća zanimljiva i važna karakteristika indenoindolovih spojeva iz sadašnjeg izuma je njihova sposobnost da stabiliziraju membrane. Indenoindole compounds are not activated to a significant extent by the action of ultraviolet radiation, which makes them candidates for use in skin care preparations. Another interesting and important characteristic of the indenoindole compounds of the present invention is their ability to stabilize membranes.

Farmakološki testovi Pharmacological tests

Najznačajnija karakteristika spojeva iz sadašnjeg izuma je njihova efikasnost kao eliminatora slobodnih radikala ili antioksidansa. Korišten je sistem za ispitivanje koji mjeri koncentraciju spojeva formula (IA) i (IB) potrebnu da bi se inhibirala peroksidacija lipida za 50% (IC50). Ispitivanje s perksidacijom lipida je opisano u daljnjem tekstu, a podaci su dati u Tablici 1. Druga opisana istraživanja uključuju test fragilnosti crvenih krvnih zrnaca koji se koristi za mjerenje stabilizacije membrana pomoću indenoindola (Tablica 2) i indenoindološku zaštitu protiv citotoksičnosti N-metil-N 1-nitro-N-nitrozoguanidina (MNNG) u hepatocitima štakora (Tablica 3). MNNG je visoko citotoksični agens, čiji mehanizam djelovanja može uključivati destabilizaciju membrana posredovanu slobodnim radikalima. The most significant characteristic of the compounds of the present invention is their effectiveness as free radical scavengers or antioxidants. A test system was used that measures the concentration of compounds of formulas (IA) and (IB) required to inhibit lipid peroxidation by 50% (IC50). The lipid peroxidation assay is described below, and data are provided in Table 1. Other studies described include a red blood cell fragility assay used to measure membrane stabilization by indenoindole (Table 2) and indenoindole protection against N-methyl-N cytotoxicity 1-nitro-N-nitrosoguanidine (MNNG) in rat hepatocytes (Table 3). MNNG is a highly cytotoxic agent, whose mechanism of action may involve free radical-mediated membrane destabilization.

1. Peroksidacija lipida zavisna od askorbuta/Fe2+ 1. Lipid peroxidation dependent on ascorbute/Fe2+

Za sistem fero/askorbatne peroksidacije lipida, 6.25 ml 0.1 M kalij fosfatnog (KP i), pH 7.4 dodano je na 12.5 mg sušenih sojinih fosfolipida. Nakon propuhavanja argonom tokom 2 minute, suspenzija je zaptivena s pet slojeva Parafilma i izložena ultrazvuku sve dok suspenzija nije postala slobodna. Konačna reakcijska smjesa se sastoji od 200 µg/ml fosfolipida, 10 µM FeNH4 (SO4)2 ili Fe (NH4)2 (SO4)2 i 100 µM askorbinske kiseline u 0.1 M KP i (pH 7.4), kao i od antioksidansa koji se testira otopljenog u acetonu ili DMSO. Opseg nosača nikada nije prelazio 1% ukupnog opsega. Reakcija je započeta dodatkom askorbinske kiseline i čelika. Reakcija je vršena na sobnoj temperaturi u mućkanom vodenom kupatilu tokom 30 minuta i zatim je zaustavljena dodatkom 10 µM 0.5 M butiliranog hidroksitoluola u DMSO. Gornja procedura i kasnije određivanje materijala reaktivnog sa 2-tiobarbiturnom kiselinom opisani su u: Shertzer, H.G. i suradnici, Biochem. Pharmacol. 37, 333 (1988). Tablica 1 prikazuje djelovanje indenoindola i α-tokoferola na askorbat/Fe2+ -zavisnu peroksidaciju lipida. For the ferrous/ascorbate lipid peroxidation system, 6.25 ml of 0.1 M potassium phosphate (KP i), pH 7.4 was added to 12.5 mg of dried soy phospholipids. After purging with argon for 2 minutes, the suspension was sealed with five layers of Parafilm and exposed to ultrasound until the suspension became free. The final reaction mixture consists of 200 µg/ml phospholipids, 10 µM FeNH4 (SO4)2 or Fe (NH4)2 (SO4)2 and 100 µM ascorbic acid in 0.1 M KP i (pH 7.4), as well as antioxidants that tests dissolved in acetone or DMSO. The girth of the carrier never exceeded 1% of the total girth. The reaction was initiated by the addition of ascorbic acid and steel. The reaction was carried out at room temperature in a shaking water bath for 30 minutes and was then stopped by the addition of 10 µM of 0.5 M butylated hydroxytoluene in DMSO. The above procedure and subsequent determination of material reactive with 2-thiobarbituric acid is described in: Shertzer, H.G. et al., Biochem. Pharmacol. 37, 333 (1988). Table 1 shows the effect of indenoindole and α-tocopherol on ascorbate/Fe2+-dependent lipid peroxidation.

Tablica 1 Table 1

[image] [image]

2. Stabilizacija membrana u crvenim krvnim zrncima 2. Stabilization of membranes in red blood cells

Učinak indenoindolovih spojeva na stabilizaciju membrana istraživano je testom fragilnosti crvenih krvnih zrnac. Štakori su anestezirani sa 65 mg fenobarbitala po kg tjelesne težine intraperitonealnom injekcijom. Uzorci krvi su uzeti u špricu s heparinom iz lijeve pretkomore i razblaženi 20x s puferom koji sadrži 140 mM NaCl, 10 mM natrijevog citrata i 5 mM glukoze (pH 7.4) na 0°C: Razblažena krv čuvana je na ledu. U kivete od 4 ml koje sadrži 10 µl antioksidansa otopljenog u DMSO kao nosaču dodane su alikvote od po 0.75 ml krvi. Nakon 1 minute lakog miješanja, u kivete je jakim pipetiranjem dodano po 0.75 ml 0.9% NaCl ili H2O, pa je mjerena aposrbanca na 656 nm pomoću Beckman DU-70 spektrofotometra. Kada je voda dodavana u odsutnosti stabilizatorskog sredstva, aposrbanca je u roku od 15 sekundi opala na 0.8. Dodavanje NaCl umjesto vode dalo je aposrbancu od 2.2 koja se ne mijenja s vremenom. U prisutnosti rastućih koncentracija stabilizatorskih kemikalija, smanjenje aposrbance nakon dodavanja vode bilo je niže. Postotna zaštita protiv osmolize dobivena je iz jednadžbe [E(2.2-0.8) - A/2.2-0.8] x 100%, gdje je A = 2.2 minus pad aposrbance kad se voda dodaje u prisutnosti poznate koncentracije kemikalije. Postotna zaštita zatim se nanosi na grafikon u odnosu na različite koncentracije kemikalija koje se istražuju. Vrijednost zaštićenog indeksa fragilnosti crvenih krvnih zrnaca (RBC-PIV) predstavlja linearni regresivni nagib ove krivulje, izražen u postocima zaštite proziv osmolize po svakom µM zaštitnog sredstva. Tablica 2 prikazuje vrijednosti RBC-PIV za različite indenoindole i α-tokoferol. The effect of indenoindole compounds on membrane stabilization was investigated by the fragility test of red blood cells. Rats were anesthetized with 65 mg of phenobarbital per kg of body weight by intraperitoneal injection. Blood samples were taken in a syringe with heparin from the left atrium and diluted 20x with a buffer containing 140 mM NaCl, 10 mM sodium citrate and 5 mM glucose (pH 7.4) at 0°C: Diluted blood was stored on ice. Aliquots of 0.75 ml of blood were added to 4 ml cuvettes containing 10 µl of antioxidant dissolved in DMSO as a carrier. After 1 minute of gentle mixing, 0.75 ml of 0.9% NaCl or H2O was added to the cuvettes by vigorous pipetting, and the absorbance was measured at 656 nm using a Beckman DU-70 spectrophotometer. When water was added in the absence of a stabilizing agent, the absorbance dropped to 0.8 within 15 seconds. Addition of NaCl instead of water gave an absorban of 2.2 that does not change with time. In the presence of increasing concentrations of stabilizing chemicals, the decrease in absorbance after water addition was lower. The percent protection against osmolysis is obtained from the equation [E(2.2-0.8) - A/2.2-0.8] x 100%, where A = 2.2 minus the drop in protection when water is added in the presence of a known concentration of the chemical. The percent protection is then plotted against the various concentrations of the chemicals being investigated. The value of the protected index of fragility of red blood cells (RBC-PIV) represents the linear regression slope of this curve, expressed in percentages of protection against osmolysis for each µM of protective agent. Table 2 shows RBC-PIV values for different indenoindoles and α-tocopherol.

Tablica 2 Table 2

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3. Zaštita protiv citostatičnog djelovanja MNNG u hepatocitima 3. Protection against the cytostatic effect of MNNG in hepatocytes

Zaštitno djelovanje indenoindola na citotoksičnost izazvanu s MNNG istraživano je na hepatocitima štakora. Hepatociti su pripremljeni tretiranjem kolagenazom kao što su prvobitno opisali Zahlteni Stratman (Zahlten, R:N: i Stratman, F.W., Arch. Biochem. Biophys. 163, 600 (1988)), s modifikacijom Reitman-a i suradnika (Reitman, F.A., Shertzer, H.G. i Berger, M.L., Biochem. Pharmacol. 37, 3183 (1988)). Korišteni su štakori tipa Sprague-Dawley. Kako bi se izboljšala sposobnost preživljavanja, ćelije su centrifugirane kroz 0.508 g/ml Na2HPO4 i 1.5 mM KH2 PO4 (pH 7.4). Istraživana zaštitna sredstva su dodavana ćelijama u obliku otopine u DMSO, pri čemu konačne koncentracije DMSO nikada nisu prelazile 5 µl/ml suspenzije ćelija. MNNG je dodavan do koncentracije od 0.5 mM kao otopina u etanolu, što daje konačnu koncentraciju etanola od 1%; sam etanol nije imao nikakvo djelovanje. Sposobnost preživljavanja je mjerena kao postotak ćelija koje isključuju 0.2% tripan plavo. Zaštitno djelovanje indenoindola i α-tokoferil-acetata na citotoksičnost prikazano je u tablici 3. Vrijednosti predstavljaju količinu spojeva potrebnu da bi se vrijeme u kojem MNNG ubije 50% ćelija produžilo za 1 sat. The protective effect of indenoindole on MNNG-induced cytotoxicity was investigated in rat hepatocytes. Hepatocytes were prepared by collagenase treatment as originally described by Zahlten Stratman (Zahlten, R:N: and Stratman, F.W., Arch. Biochem. Biophys. 163, 600 (1988)), with modification by Reitman et al. (Reitman, F.A., Shertzer, H.G. and Berger, M.L., Biochem. Pharmacol. 37, 3183 (1988)). Sprague-Dawley type rats were used. To improve viability, cells were centrifuged through 0.508 g/ml Na2HPO4 and 1.5 mM KH2 PO4 (pH 7.4). The investigated protective agents were added to the cells as a solution in DMSO, whereby the final concentrations of DMSO never exceeded 5 µl/ml of the cell suspension. MNNG was added to a concentration of 0.5 mM as a solution in ethanol, giving a final ethanol concentration of 1%; ethanol alone had no effect. Viability was measured as the percentage of cells that excluded 0.2% trypan blue. The protective effect of indenoindole and α-tocopheryl acetate on cytotoxicity is shown in Table 3. Values represent the amount of compounds required to increase the time at which MNNG kills 50% of cells by 1 hour.

Tablica 3 Table 3

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Claims

1. Indenoindolovi spojevi formule (IA) ili (IB): [image] gdje je R vodik, alkil grupa ili COR 15; R1, R2, R11 i R12 su nezavisno izabrani od vodika ili nižih alkil grupa; R3, R4, R5 i R6 su nezavisno izabrani od vodika, hidroksi, halogena, nižih alkil grupa ili nižih alkoksi grupa, mono-ili di-nižih alkilamino grupa, NH 2 ili NR 13 COR 14; R7, R8, R9 i R10 su nezavisno izabrani od vodika, hidroksi, nižih alkil grupa, nižih alkoksi grupa, mono-ili di-nižih alkilamino grupa, NH 2 ili NR 13 COR 14; R13, R14 i R15 su nezavisno izabrani od vodika ili nižih alkil grupa: pod uvjetom da (i) kada u formuli (IA) R predstavlja metil bar jedan od R1 do R12 bude različit od vodika; (i) (ii) kada u formuli (IA) R predstavlja vodik i R11 je etil, bar je jedan od R1 do R12 bude različit od vodika; njihovi enantiomjeri i njihove soli.1. Indenoindole compounds of formula (IA) or (IB): [image] where R is hydrogen, an alkyl group or COR 15; R 1 , R 2 , R 11 and R 12 are independently selected from hydrogen or lower alkyl groups; R3, R4, R5 and R6 are independently selected from hydrogen, hydroxy, halogen, lower alkyl groups or lower alkoxy groups, mono- or di-lower alkylamino groups, NH 2 or NR 13 COR 14; R7, R8, R9 and R10 are independently selected from hydrogen, hydroxy, lower alkyl groups, lower alkoxy groups, mono- or di-lower alkylamino groups, NH 2 or NR 13 COR 14; R 13 , R 14 and R 15 are independently selected from hydrogen or lower alkyl groups: provided that (i) when in formula (IA) R represents a methyl bar, one of R 1 to R 12 is different from hydrogen; (i) (ii) when in formula (IA) R represents hydrogen and R11 is ethyl, at least one of R1 to R12 is different from hydrogen; their enantiomers and their salts.

2. Spoj prema zahtjevu 1, naznačen time, što bar jedna od grupa R3, R5, R7, R9, R11 i R12 predstavlja nižu alkil grupu, poželjno metil, etil ili i-propil.2. The compound according to claim 1, characterized in that at least one of the groups R3, R5, R7, R9, R11 and R12 represents a lower alkyl group, preferably methyl, ethyl or i-propyl.

3. Spoj prema zahtjevu 1 ili 2, naznačen time, što bar jedna od grupa R5 i R8 predstavlja mono-ili di-nižu alkilamino grupu, poželjno etilamino ili dietilamino.3. Compound according to claim 1 or 2, characterized in that at least one of the groups R5 and R8 represents a mono- or di-lower alkylamino group, preferably ethylamino or diethylamino.

4. Spoj prema zahtjevu 1 ili 2, naznačen time, što bar jedna od grupa R5 i R8 predstavlja hidroksi ili nižu alkoksi grupu, poželjno metoksi.4. A compound according to claim 1 or 2, characterized in that at least one of the groups R5 and R8 represents a hydroxy or lower alkoxy group, preferably methoxy.

5. Spoj prema bilo kojem od prethodnih zahtjeva, naznačen time, što su R, R1, R2, R4, R6 i R10 atomi vodika.5. A compound according to any of the preceding claims, characterized in that R, R1, R2, R4, R6 and R10 are hydrogen atoms.

6. Spoj prema zahtjevu 1, naznačen time, što predstavlja cis-4b,5,9b,10-tetrahidroindeno[1,2-b]indol, cis-4b,5,9b,10-tetrahidro-6,8-dimetilindeno[1,2-b]indol, cis-4b,5,9b,10-tetrahidro-5,8-dimetilindeno[1,2-b]indol, cis-4b,5,9b,10-tetrahidro-8-metilindeno[l,2-b]indol, cis-4b,5,9b,10-tetrahidro-4b,6,8,9b-tetrametilindeno[1,2-b]indol, cis-4b,5,9b,10-tetrahidro-8-izopropilindeno[1,2-b]indol, cis-4b,5,9b,10-tetrahidro-8-metoksi-5-metilindeno[l,2-b]indol, cis-4b,5,9b,10-tetrahidro-8-metoksiindeno[1,2-b]indol, cis-4b,5,9b,10-tetrahidro-10,10-dimetilindeno[1,2-b]indol, cis-4b,5,9b,10-tetrahidro-9b-metilindeno[1,2-b]indol, cis-4b, 5,9b,10-tetrahidro-4b,9b-dimetilindeno[1,2-b]indol, cis-4b,5,9b,10-tetrahidro-4b,5,9b-trimetilindeno[1,2-b]indol, cis-4b,5,9b,10-tetrahidro-2-metoksi-1,3-dimetilindeno[1,2-b]indol, cis-4b, 5,9b,10-tetrahidro-2-metoksi-1,3-dimetil-8-izopropilindeno[1,2-b]indol, cis-4b,5,9b,10-tetrahidro-4b-metilindeno[1,2-b]indol, cis-4b,5,9b,10-tetrahidro-2-hidroksi-,3-dimetil-8-izopropilindeno[1,2-b]indol, cis-4b, 5,9b,10-tetrahidro-2-hidroksi-1,3-dimetilindeno[1,2-b]indol, cis-4b,5,9b,10-tetrahidro-4b,8,9b-trimetilindeno[l,2-b]indol, cis-4b,5,9b,10-tetrahidro-8-izopropil-4b,9b-dimetilindeno[1,2-b]indol, cis-4b,5,9b,10-tetrahidro-8-izopropil-4b-metilindeno[1,2-b]indol, cis-4b, 5,9b,10-tetrahidro-2,8-dimetoksi-l,3-dimetilindeno[1,2-b]indol, cis-4b,5,9b,10-tetrahidro-4b,5,8,9b-tetrametilindeno[1,2-b]indol, cis-4b,5,9b,10-tetrahidro-terc-butilindeno[1,2-b]indol, cis-4b,5,9b, 10-tetrahidro-8-metoksi-7,9-dimetilindeno[1,2-b]indol, cis-4b,5,9b,10-tetrahidro-8-metoksi-6-metilindeno[1,2-b]indol, cis-4b,5,9b,10-tetrahidro-8-dietilamino-5-etilindeno[1,2-b]indol, cis-4b,5,9b,10-tetrahidro-2-dietilaminoindeno[1,2-b]indol, cis-4b, 5 , 9b, 10-tetrahidro-8-terc-butil-4b-metilindeno[1,2-b]indol, cis-4b,5,9b,10-tetrahidro-8-floroindeno[1,2-b]indol, cis-5,5a,6,10b-tetrahidroindeno[2,1-b]indol, cis-5,5a,6,10b-tetrahidro-9-metoksiindeno[2,1-b]indol ili cis-5,5a,6,10b-tetrahidro-9-izopropilindeno[2,1-b]indol.6. A compound according to claim 1, characterized in that it represents cis-4b,5,9b,10-tetrahydroindeno[1,2-b]indole, cis-4b,5,9b,10-tetrahydro-6,8-dimethylindeno[1,2-b]indole, cis-4b,5,9b,10-tetrahydro-5,8-dimethylindeno[1,2-b]indole, cis-4b,5,9b,10-tetrahydro-8-methylindeno[1,2-b]indole, cis-4b,5,9b,10-tetrahydro-4b,6,8,9b-tetramethylindeno[1,2-b]indole, cis-4b,5,9b,10-tetrahydro-8-isopropylindeno[1,2-b]indole, cis-4b,5,9b,10-tetrahydro-8-methoxy-5-methylindeno[1,2-b]indole, cis-4b,5,9b,10-tetrahydro-8-methoxyindeno[1,2-b]indole, cis-4b,5,9b,10-tetrahydro-10,10-dimethylindeno[1,2-b]indole, cis-4b,5,9b,10-tetrahydro-9b-methylindeno[1,2-b]indole, cis-4b, 5,9b,10-tetrahydro-4b,9b-dimethylindeno[1,2-b]indole, cis-4b,5,9b,10-tetrahydro-4b,5,9b-trimethylindeno[1,2-b]indole, cis-4b,5,9b,10-tetrahydro-2-methoxy-1,3-dimethylindeno[1,2-b]indole, cis-4b, 5,9b,10-tetrahydro-2-methoxy-1,3-dimethyl-8-isopropylindeno[1,2-b]indole, cis-4b,5,9b,10-tetrahydro-4b-methylindeno[1,2-b]indole, cis-4b,5,9b,10-tetrahydro-2-hydroxy-,3-dimethyl-8-isopropylindeno[1,2-b]indole, cis-4b, 5,9b,10-tetrahydro-2-hydroxy-1,3-dimethylindeno[1,2-b]indole, cis-4b,5,9b,10-tetrahydro-4b,8,9b-trimethylindeno[1,2-b]indole, cis-4b,5,9b,10-tetrahydro-8-isopropyl-4b,9b-dimethylindeno[ 1,2-b]indole, cis-4b,5,9b,10-tetrahydro-8-isopropyl-4b-methylindeno[1,2-b]indole, cis-4b, 5,9b,10-tetrahydro-2,8-dimethoxy-1,3-dimethylindeno[1,2-b]indole, cis-4b,5,9b,10-tetrahydro-4b,5,8,9b-tetramethylindeno[1,2-b]indole, cis-4b,5,9b,10-tetrahydro-tert-butylindeno[1,2-b]indole, cis-4b,5,9b, 10-tetrahydro-8-methoxy-7,9-dimethylindeno[1,2-b]indole, cis-4b,5,9b,10-tetrahydro-8-methoxy-6-methylindeno[1,2-b]indole, cis-4b,5,9b,10-tetrahydro-8-diethylamino-5-ethylindeno[1, 2-b]indole, cis-4b,5,9b,10-tetrahydro-2-diethylaminoindeno[1,2-b]indole, cis-4b, 5, 9b, 10-tetrahydro-8-tert-butyl-4b-methylindeno[1,2-b]indole, cis-4b,5,9b,10-tetrahydro-8-fluoroindeno[1,2-b]indole, cis-5,5a,6,10b-tetrahydroindeno[2,1-b]indole, cis-5,5a,6,10b-tetrahydro-9-methoxyindeno[2,1-b]indole or cis-5,5a,6,10b-tetrahydro-9-isopropylindeno[2,1-b]indole.

7. Spoj prema zahtjevu 1, naznačen time, što predstavlja cis-4b, 5, 9b, 10-tetrahidro-4, 6-dimetil-8-metoksiindeno[1,2-b]indol, cis-5,53,6,10b-tetrahidro-7-metil-9-metoksiindeno [ 2,1-b] indol, ili cis-4b,5,9b,10-tetrahidro-8-metoksi-4b,6,9b-trimetilindeno[l,2-b]indol7. The compound according to claim 1, characterized in that it represents cis-4b, 5, 9b, 10-tetrahydro-4, 6-dimethyl-8-methoxyindeno[1,2-b]indole, cis-5,53,6,10b-tetrahydro-7-methyl-9-methoxyindeno[2,1-b]indole, or cis-4b,5,9b,10-tetrahydro-8-methoxy-4b,6,9b -trimethylindeno[1,2-b]indole

8. (-)cis-5,5a,6,10b-tetrahidro-7-metil-9-metoksiindeno-[2,1-b]indol.8. (-)cis-5,5a,6,10b-tetrahydro-7-methyl-9-methoxyindeno-[2,1-b]indole.

9. (+) cis-5,5a,6,10b-tetrahidro-7-metil-9-metoksiindeno[2,1-b]indol.9. (+) cis-5,5a,6,10b-tetrahydro-7-methyl-9-methoxyindeno[2,1-b]indole.

10. Indenoindolovi spojevi formule (IA) ili (IB): [image] gdje je R vodik, alkil grupa ili COR15; R1, R2, R11 i R12 su nezavisno izabrani od vodika ili nižih alkil grupa; R3, R4, R5 i R6 su nezavisno izabrani od vodika, hidroksi, halogena, nižih alkil grupa ili nižih alkoksi grupa, mono- ili di- nižih alkilamino grupa, NH2 ili NR13COR14; R7, R8, R9 i R10 su nezavisno izabrani od vodika, hidroksi, nižih alkil grupa, nižih alkoksi grupa, mono- ili di- nižih alkilamino grupa, NH2 ili NR13COR14; R13, R14 i R15 su nezavisno izabrani od vodika ili nižih alkil grupa; pod uvjetom da, kada R predstavlja COR15, barem jedan od R3 do R10 bude hidroksi ili mono- ili di- niža alkilamino grupa; njihovi enantiomjeri i njihove soli, naznačena time, što se koriste u terapeutskim metodama koje se primjenjuju na ljudskom ili životinjskom organizmu.10. Indenoindole compounds of formula (IA) or (IB): [image] where R is hydrogen, an alkyl group or COR15; R 1 , R 2 , R 11 and R 12 are independently selected from hydrogen or lower alkyl groups; R3, R4, R5 and R6 are independently selected from hydrogen, hydroxy, halogen, lower alkyl groups or lower alkoxy groups, mono- or di-lower alkylamino groups, NH2 or NR13COR14; R7, R8, R9 and R10 are independently selected from hydrogen, hydroxy, lower alkyl groups, lower alkoxy groups, mono- or di-lower alkylamino groups, NH2 or NR13COR14; R 13 , R 14 and R 15 are independently selected from hydrogen or lower alkyl groups; provided that, when R represents COR15, at least one of R3 to R10 is a hydroxy or mono- or di-lower alkylamino group; their enantiomers and their salts, indicated by the fact that they are used in therapeutic methods applied to the human or animal organism.

11. Spoj prema zahtjevu 10, naznačen time, što se koristi u liječenju izokemičnih ili reperfuzujskih povreda, tromboze i embolizma.11. Compound according to claim 10, characterized in that it is used in the treatment of isochemical or reperfusion injuries, thrombosis and embolism.

12. Spoj prema zahtjevu 10, naznačen time, što se koristi u liječenju ili prevenciji neoplazmi.12. Compound according to claim 10, characterized in that it is used in the treatment or prevention of neoplasms.

13. Spoj prema zahtjevu 10, naznačen time, što se koristi u liječenju Parkinsonove bolesti, Alzhajmerove bolesti ili starenja.13. Compound according to claim 10, characterized in that it is used in the treatment of Parkinson's disease, Alzheimer's disease or aging.

14. Spoj prema zahtjevu 10, naznačen time, što se koristi u liječenju arterioskleroze.14. Compound according to claim 10, characterized in that it is used in the treatment of arteriosclerosis.

15. Spoj prema zahtjevu 10, naznačen time, što se koristi u liječenju alergijsko/inflamatornih stanja kao što su bronhijalna astma ili reumatoidni artritis.15. Compound according to claim 10, characterized in that it is used in the treatment of allergic/inflammatory conditions such as bronchial asthma or rheumatoid arthritis.

16. Spoj prema zahtjevu 10, naznačen time, što se koristi u liječenju oštećenja izazvanih kemikalijama, zračenjem, antineoplastnim ili imunosupresivnim sredstvima.16. Compound according to claim 10, characterized in that it is used in the treatment of damage caused by chemicals, radiation, antineoplastic or immunosuppressive agents.

17. Spoj prema bilo kojem od zahtjeva 10-16, naznačen time, što radikali u formulama (IA) i (IB) imaju značenja definirana u zahtjevima 1-9.17. A compound according to any one of claims 10-16, characterized in that the radicals in formulas (IA) and (IB) have the meanings defined in claims 1-9.

18. Farmaceutski preparat, naznačen time, što sadr2i inertni razblaživač ili nosač, zajedno s aktivnim sastojkom koji predstavlja spoj iz bilo kojeg od zahtjeva 1-9, njegov enantiomjer ili njegovu farmaceutski prihvatljivu sol.18. Pharmaceutical preparation, characterized by the fact that it contains an inert diluent or carrier, together with the active ingredient representing the compound from any of claims 1-9, its enantiomer or its pharmaceutically acceptable salt.

19. Korištenje spoja formule (IA) ili (IB), definiranih u bilo kojem od zahtjeva 1-9, u proizvodnji lijekova za liječenje izokemičnih ili reperfuzijskih povreda, tromboze, embolizma, arterioskleroze, Parkinsonove bolesti, Alzhajmerove bolesti, starenja, neoplazmi, alergijskih ili inflamatornih stanja kao što su bronhijalna astma ili reumatoidni artritis, kao i oštećenja izazvana kemikalijama, zračenjem, antineoplastnim ili imunosupresivnim sredstvima.19. Use of a compound of formula (IA) or (IB), defined in any of claims 1-9, in the production of drugs for the treatment of isochemical or reperfusion injuries, thrombosis, embolism, arteriosclerosis, Parkinson's disease, Alzheimer's disease, aging, neoplasms, allergic or inflammatory conditions such as bronchial asthma or rheumatoid arthritis, as well as damage caused by chemicals, radiation, antineoplastic or immunosuppressive agents.

20. Postupak za spojeve formule (IA) ili (IB), definiranih u bilo kojem od zahtjeva 1-9, naznačen time, što se sastoji od: (a) redukcije 5,10-dihidroindeno[l,2-b]indola (DHII) [image] gdje su R, R1, R2, R3, R4, R5, R6, R7, R8, R9 i R10 kao što je definirano u formuli (IA) , čemu po potrebi prethodi N-alkiliranje izo-THII sa R-halogenidom ili R-sulfatom, pri čemu je R kao što je definirano u formuli (I); [image] gdje su R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 i R11 kao što je definirano u formuli (IA), nakon čega po potrebi slijedi N-alkiliranje s R-halogenidom ili R-sulfatom, pri čemu je R kao što je definirano u formuli (IA); (c) reakcije indolenina formule (IV) s lilijalkilima R12-Li [image] gdje su R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 i R12 kao što je definirano u formuli (IA), nakon čega po potrebi slijedi N-alkiliranje s R-halogenidom ili N-sulfatom, pri čemu je R kao što je definirano u formuli (IA); (d) redukcije 5,6-dihidroindeno[2,1-b]indola (izo-DHII), kojoj po potrebi prethodi N-alkiliranje izo-THII s R-halogenidom ili R-sulfatom, pri čemu je R kao što je definirano u formuli (IA) ; (e) za 10b-supstituirane-5,5b,6,10b-tetrahidroindeno[2,1-b]indole (IX) i njihove analoge, korištenja indan-2-ona (XII) sa supstituentom na C-3 u Fischerovoj indolizaciji s fenilhidrazinima formule (II), nakon čega slijedi reakcija intermedijera (VIII) s redukcijskim sredstvom [image] gdje su R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 i R11 kao što je definirano u formuli (IB), nakon čega po potrebi slijedi N-alkiliranje s R-halogenidom ili R-sulfatom, pri čemu je R kao što je definirano u formuli (IB); (f) za 5a,10b-supstituirane-5,5a,6,10b-tetrahidroindeno [2,1-b]indole i njihove analoge, reakcije indolenina formule (VIII) sa litij alkilima R12 Li [image] gdje su Rl, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 i R12 kao što je definirano u formuli (IB); (g) za 5-alkil THII ili 6-alkil izo-THII gdje su R1, R2, R3, R4, R5, R6, R7, R8, R9 i R10 kao što je definirano u formuli (I), N-alkiliranja odgovarajućeg 5-alkil DHII ili 6-alkil izo-DHII s R-halogenidom ili R-sulfatom; (h) za 5-alkil THII ili 6-alkil izo-THII gdje se R1, R2, R3, R4, R5, R6, R7, R8, R9 i R10 kao što je definirano u formuli (I), redukcije odgovarajućeg 5-acetil THII ili 6-acil izo-THII; (i) za THII ili izo-THII gdje su R3 - R6 i/ili R7-R10 definirani kao mono- ili di- niže alkilamino grupe, a R, R1, R2, R11 i R12 su kao što je definirano u formuli (I) , redukcije odgovarajućeg 5-acetil THII ili 6-acil izo-THII nitro komponenti, nakon čega slijedi N-alkiliranje i po potrebi kisela hidroliza. (j) za THII ili izo-THII gdje su R3-R6 i/ili R7-R10 definirani kao hidroksi, a R, R1, R2, R11 i R12 su kao što je definirano u formuli (I), eterskog dezalkiliranja odgovarajućeg alkoksi supstituiranog THII ili izo-THII spoja; ili (k) za THII ili izo-THII u kojima je R12 niža alkil grupa a R i R1-R11 us kao što je definirano u formuli (I), sekvence metaliziranja odgovarajućeg 4b-nesupstituiranog analoga, nakon čega slijedi alkiliranje s R12-halogenidom ili R12-sulfatom i finalna hidroliza.20. Process for compounds of formula (IA) or (IB), defined in any of claims 1-9, characterized in that it consists in: (a) reduction of 5,10-dihydroindeno[1,2-b]indole ( DHII) [image] where R, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are as defined in formula (IA), optionally preceded by N-alkylation of iso-THII with R-halide or R- sulfate, wherein R is as defined in formula (I); [image] where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are as defined in formula (IA), followed by N-alkylation with R-halide or R-sulfate if necessary, wherein R is as defined in formula (IA); (c) reactions of indolenes of formula (IV) with alkylalkyls R12-Li [image] where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are as defined in formula (IA), followed optionally by N-alkylation with R-halide or N- sulfate, wherein R is as defined in formula (IA); (d) reduction of 5,6-dihydroindeno[2,1-b]indole (iso-DHII), optionally preceded by N-alkylation of iso-THII with R-halide or R-sulfate, where R is as defined in formula (IA); (e) for 10b-substituted-5,5b,6,10b-tetrahydroindeno[2,1-b]indoles (IX) and their analogs, using indan-2-one (XII) with a substituent at C-3 in Fischer indolization with phenylhydrazines of formula (II), followed by the reaction of intermediate (VIII) with a reducing agent [image] where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are as defined in formula (IB), followed by N-alkylation with R-halide or R-sulfate if necessary, wherein R is as defined in formula (IB); (f) for 5a,10b-substituted-5,5a,6,10b-tetrahydroindeno [2,1-b]indoles and their analogues, reactions of indolenines of formula (VIII) with lithium alkyls R12 Li [image] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are as defined in formula (IB); (g) for 5-alkyl THII or 6-alkyl iso-THII where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are as defined in formula (I), N-alkylation of the corresponding 5-alkyl DHII or 6-alkyl iso-DHII with R-halide or R-sulfate; (h) for 5-alkyl THII or 6-alkyl iso-THII where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 as defined in formula (I), reduction of the corresponding 5- acetyl THII or 6-acyl iso-THII; (i) for THII or iso-THII where R 3 - R 6 and/or R 7 - R 10 are defined as mono- or di- lower alkylamino groups and R, R 1 , R 2 , R 11 and R 12 are as defined in formula (I ), reduction of the corresponding 5-acetyl THII or 6-acyl iso-THII nitro component, followed by N-alkylation and, if necessary, acid hydrolysis. (j) for THII or iso-THII where R 3 -R 6 and/or R 7 -R 10 are defined as hydroxy and R, R 1 , R 2 , R 11 and R 12 are as defined in formula (I), ether dealkylation of the corresponding alkoxy substituted THII or iso-THII compounds; or (k) for THII or iso-THII in which R 12 is a lower alkyl group and R and R 1 -R 11 are as defined in formula (I), sequences of metalation of the corresponding 4b-unsubstituted analogue, followed by alkylation with R 12 -halide or with R12-sulfate and final hydrolysis.

21. Preparat, naznačen time, što sadrži spoj podložan oksidacijskom raspadanju i spoj formule (IA) ili (IB): [image] gdje je R vodik, alkil grupa ili COR 15; R1, R2, R11 i R12 su nezavisno izabrani od vodika ili nižih alkil grupa; R3, R4, R5 i R6 su nezavisno izabrani od vodika, hidroksi, halogena, nižih alkil grupa ili nižih alkoksi grupa, mono- ili di- nižih alkilamino grupa, NH2 ili NR13 COR14; R7, R8, R9 i R10 su nezavisno izabrani od vodika, hidroksi, nižih alkil grupa, nižih alkoksi grupa, mono- ili di- nižih alkilamino grupa, NH2 ili NR13 COR14; R13, R14 i R15 su nezavisno izabrani od vodika ili nižih alkil grupa; pod uvjetom da, kada R predstavlja COR15, barem jedan od R3 do R10 bude hidroksi ili mono- ili di- niža alkilamino grupa; njegove enantiomjere i njegove soli.21. Preparation, characterized by the fact that it contains a compound subject to oxidative decomposition and a compound of formula (IA) or (IB): [image] where R is hydrogen, an alkyl group or COR 15; R 1 , R 2 , R 11 and R 12 are independently selected from hydrogen or lower alkyl groups; R3, R4, R5 and R6 are independently selected from hydrogen, hydroxy, halogen, lower alkyl groups or lower alkoxy groups, mono- or di-lower alkylamino groups, NH2 or NR13 COR14; R7, R8, R9 and R10 are independently selected from hydrogen, hydroxy, lower alkyl groups, lower alkoxy groups, mono- or di-lower alkylamino groups, NH2 or NR13 COR14; R 13 , R 14 and R 15 are independently selected from hydrogen or lower alkyl groups; provided that, when R represents COR15, at least one of R3 to R10 is a hydroxy or mono- or di-lower alkylamino group; its enantiomers and its salts.

22. Preparat prema zahtjevu 18, naznačen time, što u formulama (IA) i (IB) radikali imaju značenja kao što je definirano u bilo kojem od zahtjeva 1-9.22. The preparation according to claim 18, characterized in that in formulas (IA) and (IB) the radicals have meanings as defined in any of claims 1-9.

23. Metoda za stabilizaciju spoja podvrgnutog oksidacijskom raspadanju, naznačen time, što se takav spoj dovodi u kontakt sa spojem formule (IA) ili (IB) prema zahtjevu 21 ili 22.23. A method for stabilizing a compound subjected to oxidative decomposition, characterized in that such a compound is brought into contact with a compound of formula (IA) or (IB) according to claim 21 or 22.